Feedback detection for a treatment device

ABSTRACT

A system includes a focus optic configured to converge an electromagnetic radiation (EMR) beam to a focal region located along an optical axis. The system also includes a detector configured to detect a signal radiation emanating from a predetermined location along the optical axis. The system additionally includes a controller configured to adjust a parameter of the EMR beam based in part on the signal radiation detected by the detector. The system also includes a window located a predetermined depth away from the focal region, between the focal region and the focus optic along the optical axis, wherein the window is configured to make contact with a surface of a tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/688,940, entitled “Pigment Detection for a Therapeutic Device,” filedJun. 22, 2018, U.S. Provisional Application No. 62/688,913, entitled“Diffractive Optics for EMR-Based Tissue Treatment,” filed Jun. 22,2018, and U.S. Provisional Application No. 62/688,855, entitled“Selective Plasma Generation for Tissue Treatment,” filed Jun. 22, 2018.The entirety of each of these applications is incorporated by reference.

BACKGROUND

Melasma or chloasma faciei (the mask of pregnancy) is a common skincondition characterized by tan to dark gray-brown, irregular,well-demarcated macules and patches on the face. The macules arebelieved to be due to overproduction of melanin, which is taken up bythe keratinocytes (epidermal melanosis) or deposited in the dermis(dermal melanosis, melanophages). The pigmented appearance of melasmacan be aggravated by certain conditions such as pregnancy, sun exposure,certain medications (e.g., oral contraceptives), hormonal levels, andgenetics. The condition can be classified as epidermal, dermal, or mixeddepending on the location of excess melanin. Exemplary symptoms ofmelasma primarily include the dark, irregularly-shaped patches ormacules, which are commonly found on the upper cheek, nose, upper lip,and forehead. These patches often develop gradually over time.

Melasma can cause considerable embarrassment and distress. It isespecially problematic for darker skin tones and women, impacting up to30% of Southeastern Asian women, as well as many Latin American women.Only 1-in-4 to 1-in-20 affected individuals are male, depending on thepopulation study. Approximately 6 million women in the US cope withmelasma, according to the American Academy of Dermatology. Worldwide,numbers of those with melasma are estimated at 157 million people inAsia/Pacific, 58 million in Latin America, and 3 million in Europe.Melasma generally appears between ages 20-40. As no cure exists formelasma, US patients undergoing treatment for melasma currently try manydifferent types of treatment. 79% of US patient's topical medications;while, 37% use oral treatment; and, 25% use a laser.

Unlike other pigmented structures that are typically present in theepidermal region of skin (i.e., at or near the tissue surface), dermal(or deep) melasma is often characterized by widespread presence ofmelanin and melanophages in portions of the underlying dermis.Accordingly, treatment of dermal melasma (e.g., lightening of theappearance of darkened pigmented regions) can be particularlychallenging because of the greater difficulty in accessing and affectingsuch pigmented cells and structures located deeper within the skin.Accordingly, conventional skin rejuvenation treatments such as facialpeels (laser or chemical), dermabrasion, topical agents, and the like,which primarily affect the overlying epidermis (and are often the firstcourse of treatment for melasma), may not be effective in treatingdermal melasma.

Additionally, up to 50% of melasma patients also experience otherhyperpigmentation problems. Among all pigmentary disorders, melasma isthe one for which the largest proportion of patients are likely to visita dermatologist. The management of this disorder remains challenginggiven the incomplete understanding of the pathogenesis, its chronicity,and recurrence rates. After treatment, the melasma may recur, oftenworse than prior to treatment. And, topical treatments which may work intreating epidermal melasma fail to effectively treat dermal or mixedmelasma.

SUMMARY

It has been observed that application of light or optical energy ofcertain wavelengths can be strongly absorbed by pigmented cells, therebydamaging them. However, an effective treatment of dermal melasma usingoptical energy introduces several obstacles. For example, pigmentedcells in the dermis must be targeted with sufficient optical energy ofappropriate wavelength(s) to disrupt or damage them, which may releaseor destroy some of the pigmentation and reduce the pigmented appearance.However, such energy can be absorbed by pigment (e.g., melanin) in theoverlying skin tissue, such as the epidermis and upper dermis. Thisnear-surface absorption can lead to excessive damage of the outerportion of the skin, and insufficient delivery of energy to the deeperdermis to affect the pigmented cells therein. Moreover, moderate thermalinjury to melanin containing melanocytes located in the basal layer ofthe epidermis can trigger an increase in the production of melanin(e.g., hyperpigmentation) and severe thermal damage to the melanocytescan trigger a decrease in the production of melanin (e.g.,hypopigmentation).

The Pigmentary Disorders Academy (PDA) evaluated the clinical efficacyof different types of melasma treatment in an attempt to gain aconsensus opinion on treatment. Their efforts were published in a papertitled “Treatment of Melasma” by M. Rendon et al. published in TheJournal of the American Academy of Dermatology in May 2006. Rendon etal. reviewed literature related to melasma treatment for the 20 yearsprior and made determinations based upon their review. Rendon et al.determined that “The consensus of the group was that first line therapyfor melasma should consist of effective topical therapies, mainly fixedtriple combinations.” And, that “[l]asers should rarely be used in thetreatment of melasma and, if applied, skin type should be taken intoaccount.”

A criticism of Rendon et al.'s comprehensive report on melasma treatmentcould be that it is dated, having been published in 2006. A more recentarticle by M. Sadeghpour et al. published in 2018 in Advances inCosmetic Surgery entitled “Advances in the Treatment of Melasma”attempts to review current melasma treatment modalities. Sadeghpour etal. likewise conclude that “Topical therapy remains the gold standardfor first-line therapy for melasma using broad-spectrum sunscreens andeither hydroquinone 4% cream, tretinoin, or triple-combination creams.”Sadeghpour et al. note that dermal melasma is more difficult to treat“because destruction of these melanosomes is often accompanied bysignificant inflammation that in turn stimulates further melanogenesis.”

Therefore there is a large unmet need for a more efficacious and safetreatment for melasma and other hard to treat pigmentary disorders.

Approaches have been developed that involve application of opticalenergy to small, discrete treatment locations in the skin that areseparated by healthy tissue to facilitate healing. Accurately targetingthe treatment locations (e.g., located in dermal layer) with desirablespecificity while avoiding damage to healthy tissue around the treatmentlocation (e.g., in the epidermal layer) can be challenging. Thisrequires, for example, an optical system with high numerical aperture(NA) for focusing a laser beam to a treatment location. The high NAoptical system delivers a sufficiently high in-focus fluence (i.e.,energy density) to the dermis, while maintaining a sufficiently lowout-of-focus fluence in the epidermis. U.S. Patent ApplicationPublication No. 2016/0199132, entitled “Method and Apparatus forTreating Dermal Melasma” has shown this technique to be advantageous fortreatment of dermal pigmentation including Melasma in research settings.

However, this technique requires that a focal region formed by the highNA optical system be located precisely (e.g., within a tolerance ofabout +/−25 μm) at a depth within a target tissue. For example,melanocytes are typically located within a basal layer of the epidermisat a depth of about 100 μm. Dermal melanophages responsible for deepmelasma can be present in the upper dermis just beneath the basal layerof the epidermis (e.g., 50 μm below). Therefore, a difference in focalregion depth of a few-tens of micrometers can become the differencebetween effectively treating dermal pigmentation and inadvertentlydamaging melanocytes and potentially causing debilitating cosmeticresults (e.g., hypopigmentation). In part for this reason, an EMR-basedsystem that effectively treats dermal pigmentation has yet to be madecommercially available.

Therefore, it is desirable to develop an EMR-based treatment system thatreliably locates a focal region to a prescribed depth within a toleranceof tens of micrometers (e.g., about ±100 μm, about ±10 μm, about ±1 μm,etc.) Further, it can be desirable that the EMR-based treatment systemachieve this performance in part through calibration, for example byperiodically placing the focal region at a reference having a knowndepth. Furthermore, it can be desirable that the reference used duringcalibration be used during treatment. For example, the reference caninclude an interface that establishes a robust contact with thetreatment region and stabilizes the treatment region.

Some developed approaches for dermal pigment treatment, like thoseoutlined by Anderson et al., can employ selective thermionic plasmageneration as a means of treatment. In these cases, laser fluence at afocal region within the dermis is above a thermionic plasma threshold(e.g., 10⁹ W/cm²), but below an optical breakdown threshold (e.g., 10¹²W/cm²). This causes plasma formation selectively when the focal regionis located at a pigmented tissue (e.g., melanin) within the dermiswithout generating a plasma in unpigmented tissue in the dermis orpigmented epidermal tissue above the focal region. The selectivelyformed thermionic plasma disrupts or damages the pigment and surroundingtissue. This disruption ultimately leads to clearing of the dermalpigment. Therefore, presence of plasma during treatment within a tissuebeing treated can be indicative of efficacious treatment in someembodiments. As parameter selection for laser-based skin treatmentsoften depends on skin type and is therefore dependent upon eachindividual patient, the presence of plasma may be used as an indicationthat correct treatment parameters have been achieved. This feedback istherefore desirable for successful treatment of a condition, such asmelasma, in populations that are generally underserved by laser-basedtreatment (e.g., those with darker skin types).

Alternatively, in some cases, properties of a detected plasma mayindicate that the treatment is having an adverse effect. For example, insome embodiments a transmissive window is placed onto a skin beingtreated to reference the skin and keep it from moving during treatment.It is possible for treatment to fail when the laser beam etches thewindow. Etching of the window prevents further efficient transmission ofthe laser to the tissue and often coincides with very bright plasmaformation in the window itself. If treatment continues with an etchedwindow it is likely that heat accumulation within the window will causedamage to the epidermis of the skin (e.g., burning and blistering). Itis therefore advantageous to employ feedback to detect plasma formationwithin the window and stop treatment when it occurs.

From the foregoing, it can be understood that plasma formation duringtreatment can be both advantageous and deleterious to treatment. Thus,systems and methods that provide plasma detection can detect propertiesof the plasma and distinguish between plasma beneficial to tissuetreatment and plasma detrimental to tissue treatment continuously inreal-time.

It can be desirable in some embodiments to image the tissue beingtreated from the perspective of the treatment device and project thisview onto a screen for viewing by the practitioner. In one aspect,placement of a treatment device typically occludes a practitioner's viewof the tissue being treated. Thus, tissue imaging can facilitateaccurate placement of the treatment device for targeting affectedtissue. Additionally, as the goal of treatment of many pigmentaryconditions is aesthetic (e.g., improve the appearance of the skin) itimages of the skin can be consistently acquired under repeatable imagingconditions (e.g., lighting and distance) during imaging so that resultsof treatment may be ascertained.

It has long been the hope of those suffering with pigmentary conditions,such as melasma, that an EMR-based treatment for their condition be madewidely available. Accordingly, as discussed in greater detail below, anEMR-based treatment system is provided that provides repeatable depthpositioning of the focal region within a target tissue. The disclosedsystems and methods can also detect and record plasma events in order todocument and track treatment safety and effectiveness and image thetreated tissue to accurately deliver EMR to the treatment region. Thesecapabilities address a number of technical problems currently preventingwidespread successful treatment of dermal pigmentation and other hard totreat skin conditions with EMR-based systems.

In one embodiment, a system is provided. The system can include a focusoptic, a detector, a controller, and a window. The focus optic can beconfigured to converge an electromagnetic radiation (EMR) beam to afocal region located along an optical axis. The detector can beconfigured to detect a signal radiation emanating from a predeterminedlocation along the optical axis. The controller can be configured toadjust a parameter of the EMR beam based in part on the signal radiationdetected by the detector. The window can be located a predetermineddepth away from the focal region, between the focal region and the focusoptic along the optical axis. The window can be configured to makecontact with a surface of a tissue.

In another embodiment, the EMR beam can be configured to generate aplasma at the predetermined location along the optical axis. The signalradiation can emanate from the plasma.

In another embodiment, the signal radiation can emanate from aninteraction between the EMR beam and the window.

In another embodiment, the focus optic can be further configured toimage the signal radiation detected by the detector.

In another embodiment, the system can further include a scannerconfigured to scan the focal region from a first region within thetissue to a second region within the tissue.

In another embodiment, the EMR beam can be further configured togenerate a thermionic plasma at the focal region.

In another embodiment, the window can be further configured to transmitthe EMR beam.

In another embodiment, the focus optic can be further configured toconverge the EMR beam at a numerical aperture (NA) of at least 0.3.

In another embodiment, the parameter of the EMR beam can include atleast one of: a pulse energy, a repetition rate, a pulse duration, afocal region location, a focal region size, a wavelength, or a power.

In another embodiment, the signal radiation can include at least one of:a visible light, an infrared light, an acoustic signal, an ultrasonicsignal, a radio signal, or a temperature.

In an embodiment, a method is provided. The method can includecontacting, using a window, a surface of a tissue. The method can alsoinclude converging, using a focus optic, an electromagnetic radiation(EMR) beam to a focal region located along an optical axis. The methodcan further include detecting, using a detector, a signal radiationemanating from a location along the optical axis. The method canadditionally include adjusting, using a controller, a parameter of theEMR beam based in part on the detected signal radiation. The method canalso include positioning the focal region within the tissue at apredetermined distance from the surface of the tissue.

In another embodiment, the method can further include generating, usingthe EMR beam, a plasma at the location along the optical axis. Thesignal radiation can emanate from the plasma.

In another embodiment, the method can further include directing theconverging EMR beam incident upon the window. The signal radiation canemanate from an interaction between the EMR beam and the window.

In another embodiment, the method further includes imaging, using thefocus optic, the signal radiation incident the detector.

In another embodiment, the method further includes scanning, using ascanner, the focal region from a first region within the tissue to asecond region within the tissue.

In another embodiment, the method further includes generating, using theEMR beam, a thermionic plasma at the focal region.

In another embodiment, the method further includes transmitting the EMRbeam through the window.

In another embodiment, the focus optic is further configured to convergethe EMR beam at a numerical aperture (NA) of at least 0.3.

In another embodiment, the parameter of the EMR beam can include atleast one of: a pulse energy, a repetition rate, a pulse duration, afocal region location, a focal region size, a wavelength, or a power.

In another embodiment, the signal radiation includes at least one of: avisible light, an infrared light, an acoustic signal, an ultrasonicsignal, a radio signal, or a temperature.

In one embodiment, a system is provided. The system can include a focusoptic, a window, an optical detector, a controller, and a stage. Thefocus optic can be configured to focus an electromagnetic radiation(EMR) beam to a focal region located along an optical axis. The windowcan intersect the optical axis and it can be configured to contact asurface of a tissue. The optical detector can be configured to detect asignal radiation emanating from an interaction of the EMR beam with thewindow. The controller can be configured to determine a referenceposition where a portion of the focal region is substantially coincidentwith a surface of the window. The stage can be configured to translatethe focal region to a treatment position that is located at apredetermined distance from the reference position.

In another embodiment, the focus optic and the stage can be configuredto position the treatment position within a tissue.

In another embodiment, the treatment position can be located within adermal tissue.

In another embodiment, the EMR beam can be configured to generate athermionic plasma at the focal region.

In another embodiment, the EMR beam can include a pulse having a pulseduration of at least 1 picosecond.

In another embodiment, the focus optic can be further configured toimage the signal radiation incident the detector.

In another embodiment, the controller can be further configured todetermine the reference position by determining a transverse width ofthe EMR beam incident the surface of the window, based upon the signalradiation, and translating the focal region until the transverse widthhas a minimum value.

In another embodiment, the detector can be further configured to detectan intensity of the signal radiation, and the controller can be furtherconfigured to determine the reference position by translating the focalregion until the intensity of the signal radiation has a maximum value.

In another embodiment, the focus optic can be further configured toconverge a second EMR beam to a second focal region. The second EMR beamcan have at least one of: a wavelength that is identical to a wavelengthof the EMR beam or a wavelength that is different to the wavelength ofthe EMR beam. The second EMR beam can be configured to effect a desiredchange in the tissue.

In another embodiment, the stage can be configured to translate thefocal region by translating at least one of: the focus optic, one ormore optical elements, and the window.

In an embodiment a method is provided that includes converging, using afocus optic, an electromagnetic radiation (EMR) beam to a focal regionlocated along an optical axis. The method can also include detecting,using a detector, a signal radiation emanating from an interaction ofthe EMR beam and a window intersecting the optical axis. The method canfurther include determining, using a controller, a reference positionalong the optical axis based upon the detected signal radiation. At thereference position, a portion of the focal region can be substantiallycoincident with a surface of the window. The method can further includetranslating the focal region to a treatment position located apredetermined distance from the reference position.

In another embodiment, the method can further include contacting, usingthe window, a surface of a tissue, such that the treatment position canbe located within the tissue.

In another embodiment, the predetermined distance can be configured tolocate the treatment position within a dermal tissue.

In another embodiment, the EMR beam can be configured to generate athermionic plasma in the focal region.

In another embodiment, the EMR beam can include a pulse having a pulseduration of at least 1 picosecond.

In another embodiment, detecting the signal radiation can furtherinclude imaging, using the focus optic, the signal radiation incidentthe detector.

In another embodiment, determining the reference position can furtherinclude determining, using the controller, a transverse width of the EMRbeam incident the surface of the window, based upon the signalradiation, and translating the focal region along the optical axis untilthe transverse width has a minimum value.

In another embodiment, determining the reference position can furtherinclude detecting, using the detector, an intensity of the signalradiation, and translating the focal region until the intensity of thesignal radiation has a maximum value.

In another embodiment, the method can further include converging, usingthe focus optic, a second EMR beam to a second focal region. The secondEMR beam can have at least one of: a wavelength that is identical to awavelength of the EMR beam or a wavelength that is different to thewavelength of the EMR beam. The second EMR beam can be configured toeffect a desired change in the tissue.

In another embodiment, translating the focal region can further includetranslating at least one of the focus optic, one or more opticalelements, and the window.

In one embodiment, a system is provided and can include a radiationsource, a window, a focus optic, a scanner, a detector, and acontroller. The radiation source can be configured to generate atreatment radiation configured to effect a desired change in a tissue.The window can be configured to contact a surface of the tissue. Thefocus optic can be configured to focus the treatment radiation to afocal region configured to generate a plasma at the focal region. Thescanner can be configured to scan the focal region. The detector can beconfigured to detect a signal radiation emanating from the plasma. Thecontroller can be configured to determine if the plasma is at leastpartially located within the window, based on the detected signalradiation, and to control one or more parameters of the treatmentradiation based on the determination.

In another embodiment, the controller can be further configured todetermine one or more properties of the plasma.

In another embodiment, the one or more properties of the plasma caninclude at least one of a presence of a plasma, an intensity of aplasma, a spectral content of a plasma, and a position of a plasma.

In another embodiment, the controller can be further configured toterminate the treatment radiation based on the determination.

In another embodiment, the one or more parameters of the treatmentradiation can include at least one of an energy per pulse, a repetitionrate, a position of a focal region, and a size of a focal region.

In another embodiment, the desired change in the tissue can includegeneration of selective thermionic plasma in presence of a chromophore.

In another embodiment, the controller can be further configured torecord a property of the signal radiation.

In another embodiment, the controller can be further configured torecord a first property of a first signal radiation emanating from afirst plasma at a first location, map the first property to a coordinatefor the first location, record a second property of a second signalradiation emanating from a second plasma at a second location, and mapthe second property to a coordinate for the second location.

In another embodiment, the controller can be further configured todetermine if the plasma is at least partially located within the windowbased on an intensity of the signal radiation.

In another embodiment, the controller can be further configured todetermine if the plasma is at least partially located within the windowbased on a spectral component of the signal radiation.

In an embodiment, a method is provided. The method can includegenerating, with a radiation source, a treatment radiation configured toeffect a desired change in a tissue. The method can also includecontacting, using a window, a surface of the tissue. The method canfurther include focusing, with a focus optic, the treatment radiation toa focal region. The method can additionally include scanning, with ascanner, the focal region. The method can additionally includegenerating, with the treatment radiation, a plasma at the focal region.The method can also include detecting, with a detector, a signalradiation emanating from the plasma. The method can additionally includedetermining, using a controller, if the plasma is at least partiallylocated within the window, based on the detected signal radiation. Themethod can further include controlling, using the controller, one ormore parameters of the treatment radiation based on the determination.

In another embodiment, the method can further include determining, withthe controller, one or more properties of the plasma.

In another embodiment, the one or more properties of the plasma caninclude at least one of a presence of a plasma, an intensity of aplasma, a spectral content of a plasma, and a position of a plasma.

In another embodiment, the method can further include terminating, usingthe controller, the treatment radiation based on the determination.

In another embodiment, the one or more parameters of the treatmentradiation can include at least one of an energy per pulse, a repetitionrate, a position of a focal region, and a size of a focal region.

In another embodiment, the desired change in the tissue can be ageneration of a selective thermionic plasma in presence of achromophore.

In another embodiment, the method can include recording, using thecontroller, a property of the signal radiation.

In another embodiment, the method can further include recording, usingthe controller, a first property of a first signal radiation emanatingfrom a first plasma at a first location, mapping the first property to acoordinate for the first location, recording, using a data acquisitiondevice, a second property of a second signal radiation emanating from asecond plasma at a second location, and, mapping the second property toa coordinate for the second location.

In another embodiment, determining if the plasma is at least partiallylocated within the window can be based on an intensity of the signalradiation.

In another embodiment, determining if the plasma is at least partiallylocated within the window can be based on a spectral component of thesignal radiation.

In an embodiment, a system is provided and can include a radiationsource, a focus optic, a detector, and a treatment radiation. Theradiation source can be configured to illuminate a tissue with animaging radiation. The focus optic can be configured to image a view ofthe tissue. The detector can be configured to detect an image of theview of the tissue. The treatment radiation can be configured to befocused, using the focus optic, to a focal region within a targettreatment region designated based in part on the image.

The system can further include a scanner configured to scan the view toa second region of the tissue. The focus optic can be further configuredto image a second image of the view from the second region of thetissue. The detector can be further configured to detect the secondimage.

In another embodiment, the scanner can be further configured to scan thefocal region within the target treatment region.

In another embodiment, the system can further include a controllerconfigured to stitch the image and the second image into a map. The mapcan be configured to be used in the determination of at least one of: adiagnosis, a treatment plan, and a treatment parameter for the treatmentradiation.

In another embodiment, the system can further include a windowconfigured to contact a surface of the tissue, such that the focalregion is located a predetermined depth from the surface of the tissue.

In another embodiment, the system can further include a controllerconfigured to record the image.

In another embodiment, the system can further include a controllerconfigured to control a parameter of the treatment radiation based inpart on the image.

In another embodiment, the treatment radiation can be configured toselectively generate a plasma at a chromophore proximal the focalregion.

In another embodiment, the focus optic can be further configured toimage the first image using at least one of: microscopic imaging, widefield of view imaging, and reflectance confocal imaging.

In another embodiment, the system can further include a displayconfigured to display the image.

In an embodiment, a method is provided. The method can includeilluminating, using a radiation source, a tissue with an imagingradiation. The method can also include imaging, using a focus optic, animage of a view of the tissue. The method can additionally includedetecting, using a detector, the image. The method can also includedesignating a target treatment region of the tissue based in part on theimage. The method can further include converging, using the focus optic,a treatment radiation to a focal region within the target treatmentregion.

In another embodiment, the method can further include scanning, using ascanner, the view to a second region of the tissue, imaging, using thefocus optic, a second image of the view from the second region of thetissue, and detecting, using the detector, the second image.

In another embodiment, the method can further include scanning, usingthe scanner, the focal region within the target treatment region.

In another embodiment, the method can further include stitching theimage and the second image together into a map.

In another embodiment, the method can further include determining fromthe map at least one of: a diagnosis, a treatment plan, and a treatmentparameter for the treatment radiation.

In another embodiment, the method can further include contacting, usinga window, a surface of a tissue, such that the focal region is located apredetermined depth from the surface of the tissue.

In another embodiment, the method can further include recording, using acontroller, the image.

In another embodiment, the method can further include controlling, usingthe controller, a parameter of the treatment radiation based in part onthe image.

In another embodiment, the treatment radiation can be configured toselectively generate a plasma at a chromophore proximal the focalregion.

In another embodiment, imaging the first image can include at least oneof: microscopic imaging, wide field of view imaging, or reflectanceconfocal imaging.

In another embodiment, the method can further include displaying, usinga display, the image.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the disclosure will be more fully understood from thefollowing detailed description taken in conjunction with theaccompanying drawings, in which:

FIG. 1 illustrates an exemplary embodiment of a treatment system,according to some embodiments;

FIG. 2 is a schematic illustration of an electromagnetic radiation (EMR)beam focused into a pigmented region of a dermal layer in skin;

FIG. 3A is an exemplary absorbance spectrum graph for melanin;

FIG. 3B is an exemplary absorbance spectrum graph for hemoglobin;

FIG. 4 illustrates a plot of the absorption coefficients of melanin andvenous blood and scattering coefficients of light in skin versuswavelength;

FIG. 5 is a schematic illustration of a treatment system, according tosome embodiments;

FIG. 6 is a schematic illustration of an optical system, according tosome embodiments;

FIG. 7 is a schematic illustration of an optical system having amicroscope attachment, according to some embodiments;

FIG. 8 is a schematic illustration of an optical system having a fibercoupler attachment, according to some embodiments;

FIG. 9 illustrates a flow chart for a plasma detection method, accordingto some embodiments;

FIG. 10 illustrates a schematic of a plasma detection system, accordingto some embodiments;

FIG. 11A is a schematic illustration of a treatment optical system,according to some embodiments;

FIG. 11B illustrates the histology of a section of a skin sample havingmelanin tattoo;

FIG. 12 illustrates spectra associated with radiation from plasmagenerated in melanin tattoo and radiation from no-plasma generated inbare skin, according to some embodiments;

FIG. 13 illustrates spectra associated with radiation from plasmagenerated in carbon tattoo and radiation from no-plasma generated inbare skin, according to some embodiments;

FIG. 14 illustrates spectra of radiation generated by plasma in a skinsample, according to some embodiments;

FIG. 15 illustrates the radiation spectra from a plasma formed using asapphire window, according to some embodiments;

FIG. 16A illustrates a front view of an exemplary version of a plasmadetection system, according to some embodiments;

FIG. 16B illustrates a cross-sectional view of an exemplary version of aplasma detection system, according to some embodiments;

FIG. 16C illustrates a detail view of an exemplary version of a plasmadetection system, according to some embodiments;

FIG. 17 illustrates a flow chart for window referencing, according tosome embodiments;

FIG. 18A illustrates schematics of a window referencing system,according to some embodiments;

FIG. 18B illustrates performance of a window referencing system,according to some embodiments;

FIG. 19 illustrates an exemplary bench prototype for confocal imaging,according to some embodiments;

FIG. 20 illustrates a maximum radiation intensity measurement, accordingto some embodiments;

FIG. 21A illustrates a front view of an exemplary version of a treatmentsystem without a removable window referencing system attached, accordingto some embodiments;

FIG. 21B illustrates a front view of an exemplary version of a treatmentsystem with a removable window referencing system attached, according tosome embodiments;

FIG. 21C illustrates a cross-sectional view of an exemplary version of atreatment system with a removable window referencing system attached,according to some embodiments;

FIG. 22A illustrates a front view of an exemplary version of a treatmentsystem without a window referencing system attached, according to someembodiments;

FIG. 22B illustrates a front view of an exemplary version of a treatmentsystem with a window referencing system attached, according to someembodiments;

FIG. 22C illustrates a cross-sectional view of an exemplary version of atreatment system with a window referencing system attached, according tosome embodiments;

FIG. 23 illustrates a flow chart for a method of imaging andradiation-based treatment, according to some embodiments;

FIG. 24 illustrates a schematic of an imaging and radiation-basedtreatment system, according to some embodiments;

FIG. 25 schematically illustrates a stitched image, according to someembodiments

FIG. 26A illustrates a front view of an exemplary version of an imagingand radiation-based treatment system, according to some embodiments;

FIG. 26B illustrates an exemplary version of an imaging andradiation-based treatment system, according to some embodiments;

FIG. 27A shows a black-and-white image taken using an exemplary versionof an imaging and radiation-based treatment system, according to someembodiments; and,

FIG. 27B shows a stitched black-and-white image including multipleimages taken using an exemplary version of an imaging andradiation-based treatment system, according to some embodiments.

It is noted that the drawings are not necessarily to scale. The drawingsare intended to depict only typical aspects of the subject matterdisclosed herein, and therefore should not be considered as limiting thescope of the disclosure. The systems, devices, and methods specificallydescribed herein and illustrated in the accompanying drawings arenon-limiting exemplary embodiments.

DETAILED DESCRIPTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Embodiments of the disclosure are discussed in detail below with respectto treatment of pigmentary conditions of the skin, such as melasma, toimprove the appearance of such a pigmentary condition. However, thedisclosed embodiments can be employed for treatment of other pigmentaryand non-pigmentary conditions and other tissue and non-tissue targetswithout limit. Examples of pigmentary conditions can include, but arenot limited to, post inflammatory hyperpigmentation (PIH), dark skinsurrounding eyes, dark eyes, café au lait patches, Becker's nevi, Nevusof Ota, congenital melanocytic nevi, ephelides (freckles) and lentigo.Additional examples of pigmented tissues and structures that can betreated include, but are not limited to, hemosiderin rich structures,pigmented gallstones, tattoo-containing tissues, and lutein, zeaxanthin,rhodopsin, carotenoid, biliverdin, bilirubin and hemoglobin richstructures. Examples of targets for the treatment of non-pigmentedstructures, tissues and conditions can include, but are not limited to,hair follicles, hair shafts, vascular lesions, infectious conditions,sebaceous glands, acne, and the like.

Methods of treating various skin conditions, such as for cosmeticpurposes, can be carried out using the systems described herein. It isunderstood that, although such methods can be conducted by a physician,non-physicians, such as aestheticians and other suitably trainedpersonnel may use the systems described herein to treat various skinconditions with and without the supervision of a physician.

Further, in the present disclosure, like-named components of theembodiments generally have similar features, and thus within aparticular embodiment each feature of each like-named component is notnecessarily fully elaborated upon. Additionally, to the extent thatlinear or circular dimensions are used in the description of thedisclosed systems, devices, and methods, such dimensions are notintended to limit the types of shapes that can be used in conjunctionwith such systems, devices, and methods. A person skilled in the artwill recognize that an equivalent to such linear and circular dimensionscan easily be determined for any geometric shape. Sizes and shapes ofthe systems and devices, and the components thereof, can depend at leaston the anatomy of the subject in which the systems and devices will beused, the size and shape of components with which the systems anddevices will be used, and the methods and procedures in which thesystems and devices will be used.

In general, high numerical aperture (NA) optical treatment systems aredescribed that can focus electromagnetic radiation (EMR) (e.g., a laserbeam) to a treatment region in a tissue. Unless otherwise noted, theterms EMR, EMR beam, and laser beam are employed interchangeably herein.The focused laser beam can deliver optical energy to the treatmentregion without harming the surrounding tissue. The delivered opticalenergy can, for example, disrupt pigmented chromophores and/or targetsin a treatment region of the dermal layer of the skin, without affectingthe surrounding regions (e.g., overlying epidermal layer, other portionsof the dermal layer, and the like). In other implementations, thedelivered optical energy can cause tattoo removal or alteration, orhemoglobin-related treatment.

Exemplary methods and devices for treating skin conditions with light oroptical energy are disclosed in U.S. Patent Application Publication No.2016/0199132, entitled “Method and Apparatus for Treating DermalMelasma,” and U.S. Provisional Application No. 62/438,818, entitled“Method and Apparatus for Selective Treatment of Dermal Melasma,” eachof which is hereby incorporated by reference herein in their entirety.

In general, systems and corresponding methods are provided for treatmentof pigmentary conditions in tissues. As discussed in greater detailbelow, the disclosed systems and methods employ electromagneticradiation (EMR), such as laser beams, to deliver predetermined amountsof energy to a target tissue. The EMR can be focused to a focal regionand the focal region can be translated or rotated in any direction withrespect to the target tissue. The predetermined amount of radiation canbe configured to thermally disrupt or otherwise damage portions of thetissue exhibiting the pigmentary condition. In this manner, thepredetermined amount of energy can be delivered to any position withinthe target tissue for treatment of the pigmentary condition such as toimprove the appearance thereof.

FIG. 1 illustrates one exemplary embodiment of a treatment system 10. Asshown, the treatment system 10 includes a mounting platform 12, emitter14, and a controller 16. The mounting platform 12 can include one ormore manipulators or arms 20. The arms 20 can be coupled to the emitter14 for performing various treatments on a target tissue 22 of a subject24. Operation of the mounting platform 12 and emitter 14 can be directedby a user, manually or using the controller 16 (e.g., via a userinterface). In certain embodiments (not shown), the emitter can have ahand-held form factor and the mounting platform 12 can be omitted.

The emitter 14 and controller 16 (and optionally the mounting platform12) can be in communication with one another via a communications link26, which can be any suitable type of wired and/or wirelesscommunications link carrying any suitable type of signal (e.g.,electrical, optical, infrared, etc.) according to any suitablecommunications protocol.

Embodiments of the controller 16 can be configured to control operationof the emitter 14. In one aspect, the controller 16 can control movementof EMR 30. As discussed in detail below, the emitter 14 can include asource 32 for emission of the EMR 30 and a scanning system 34 formanipulation of the EMR 30. As an example, the scanning system 34 can beconfigured to focus EMR 30 to a focal region and translate and/or rotatethis focal region in space. The controller 16 can send signals to thesource 32, via the communications link 26 to command the source 32 toemit the EMR 30 having one or more selected properties, such aswavelength, power, repetition rate, pulse duration, pulse energy,focusing properties (e.g., focal volume, Raleigh length, etc.). Inanother aspect, the controller 16 can send signals to the scanningsystem 34, via the communications link 26 to command the scanning system34 to move the focal region of the EMR 30 with respect the target tissue22 in one or more translation and/or rotation operations.

Embodiments of the treatment system 10 and methods are discussed hereinin the context of targets within skin tissue, such as a dermal layer.However, the disclosed embodiments can be employed for treatment of anytissue in any location of a subject, without limit. Examples of non-skintissues can include, but are not limited to, surface and sub-surfaceregions of mucosal tissues, genital tissues, internal organ tissues, andgastrointestinal tract tissues.

FIG. 2 is a schematic view of an illustration of a laser beam focusedinto a pigmented region of a dermal layer in a skin tissue. The skintissue includes a skin surface 100 and an upper epidermal layer 110, orepidermis, which can be, e.g., about 30-120 μm thick in the facialregion. The epidermis 110 can be slightly thicker in other parts of thebody. For example, in general the thickness of the epidermis can rangefrom about 30 μm (e.g., on the eyelids) to about 1500 μm (e.g., on thepalm of the hand or soles of the feet). Such epidermis may be thinner orthicker than the examples above in certain conditions of the skin, forexample psoriasis. The underlying dermal layer 120, or dermis, extendsfrom below the epidermis 110 to the deeper subcutaneous fat layer (notshown). Skin exhibiting deep or dermal melasma can include a populationof pigmented cells or regions 130 that contain excessive amounts ofmelanin. Electromagnetic radiation (EMR) 150 (e.g., a laser beam) can befocused into one or more focal regions 160 that can be located withinthe dermis 120, or the epidermis, 110. The EMR 150 can be provided atone or more appropriate wavelengths that can be absorbed by melanin. EMRwavelength(s) can be selected based on one or more criteria describedbelow.

Properties of Treatment Radiation

Determination of desirable wavelength for treatment of certain skinconditions, such as pigmentary conditions and non-pigmentary conditions,can depend on, for example, the wavelength dependent absorptioncoefficient of the various competing chromophores (e.g., chromophore,hemoglobin, tattoo ink, etc.) present in the skin. FIG. 3A is anexemplary absorbance spectrum graph for melanin. The absorption of EMRby melanin is observed to reach a peak value at a wavelength of about350 nm, and then decreases with increasing wavelength. Althoughabsorption of the EMR by the melanin facilitates heating and/ordisruption of the melanin-containing regions 130, a very high melaninabsorbance can result in high absorption by pigment in the epidermis 110and reduced penetration of the EMR into the dermis 120, or the epidermis110. As illustrated in FIG. 3A, melanin absorption is relatively high atEMR wavelengths that are less than about 500 nm. Accordingly,wavelengths less than about 500 nm may not be suitable for penetratingsufficiently into the dermis 120 to heat and damage or disrupt pigmentedregions 130 therein. Such enhanced absorption at smaller wavelengths canresult in unwanted damage to the epidermis 110 and upper (superficial)portion of the dermis 120, with relatively little unabsorbed EMR passingthrough the tissue into the deeper portions of the dermis 120.

FIG. 3B is an exemplary absorbance spectrum graph for oxygenated ordeoxygenated hemoglobin. Hemoglobin is present in blood vessels of skintissue, and can be oxygenated (HbO₂) or deoxygenated (Hb). Each form ofHemoglobin may exhibit slightly different EMR absorption properties. Asillustrated in FIG. 3B, exemplary absorption spectra for both Hb andHbO₂ indicate a high absorption coefficient for both Hb and HbO₂ at EMRwavelengths less than about 600 nm, with the absorbance decreasingsignificantly at higher wavelengths. Strong absorption of EMR directedinto skin tissue by hemoglobin (Hb and/or HbO₂) can result in heating ofthe hemoglobin-containing blood vessels, resulting in unwanted damage tothese vascular structures and less EMR available to be absorbed by themelanin when the desired treatment is a melanin-rich tissue orstructure.

The choice of an appropriate wavelength for EMR can also depend onwavelength dependent scattering profile of tissues interacting with theEMR. FIG. 4 illustrates a plot of the absorption coefficient of melaninand venous (deoxygenated) blood versus wavelength. FIG. 4 alsoillustrates a plot of the scattering coefficient of light in skin versuswavelength. Absorption in melanin decreases monotonically withwavelength. If melanin is the target of a pigmentary conditiontreatment, a wavelength having a high absorption in melanin isdesirable. This would suggest that the shorter the wavelength of light,the more efficient the treatment. However, absorption by blood increasesat wavelengths shorter than 800 nm, thereby increasing the risk ofunintentional targeting of blood vessels. In addition, as the intendedtarget can be located below the skin surface, the role of scattering byskin (e.g., dermal layer) can be significant. Scattering reduces theamount of light that reaches the intended target. The scatteringcoefficient decreases monotonically with increasing wavelength.Therefore, while a shorter wavelength can favor absorption by melanin, alonger wavelength can favor deeper penetration due to reducedscattering. Similarly, longer wavelengths are better for sparing bloodvessels due to a lower absorption by blood at longer wavelengths.

With the above considerations in mind, wavelengths can range from about400 nm to about 4000 nm, and more particularly about 500 nm to about2500 nm, can be used for selectively targeting certain structures (e.g.,melanin) in the dermis. In particular, wavelengths of about 800 nm andabout 1064 nm can be useful for such treatments. The 800 nm wavelengthcan be attractive because laser diodes at this wavelength are lesscostly and readily available. However, 1064 nm can be particularlyuseful for targeting deeper lesions due to lower scattering at thiswavelength. A wavelength of 1064 nm can also be more suitable for darkerskin types in whom there is a large amount of epidermal melanin. In suchindividuals the higher absorption of lower wavelength EMR (e.g., about800 nm) by melanin in the epidermis increases the chances of thermalinjury to the skin. Hence, 1064 nm may be a more suitable wavelength ofthe treatment radiation for certain treatments for some individuals.

Various laser sources can be used for the generation of EMR. Forexample, Neodymium (Nd) containing laser sources are readily availablethat provide 1064 nm EMR. These laser sources can operate in a pulsedmode with repetition rates in a range of about 1 Hz to 100 KHz.Q-Switched Nd lasers sources may provide laser pulses having a pulseduration of less than one nanosecond. Other Nd laser sources may providepulses having pulse durations more than one millisecond. An exemplarylaser source providing 1060 nm wavelength EMR is a 20 W NuQ fiber laserfrom Nufern of East Granby, Conn., USA. The 20 W NuQ fiber laserprovides pulses having a pulse duration of about 100 ns at a repetitionrate in the range between about 20 KHz and about 100 KHz. Another lasersource, is an Nd:YAG Q-smart 850 from Quantel of Les Ulis, France. TheQ-smart 850 provides pulses having a pulse energy up to about 850 mJ anda pulse duration of about 6 ns at a repetition rate of up to about 10Hz.

The systems described herein can be configured to focus the EMR in ahighly convergent beam. For example, the system can include a focusingor converging lens arrangement having a numerical aperture (NA) selectedfrom about 0.3 to 1 (e.g., between about 0.5 and about 0.9). Thecorrespondingly large convergence angle of the EMR can provide a highfluence and intensity in the focal region of the lens (which can belocated within the dermis) with a lower fluence in the overlying tissueabove the focal region. Such focal geometry can help reduce unwantedheating and thermal damage in the overlying tissue above the pigmenteddermal regions. The exemplary optical arrangement can further include acollimating lens arrangement configured to direct EMR from the emittingarrangement onto the focusing lens arrangement.

The exemplary optical treatment systems can be configured to focus theEMR to a focal region having a width or spot size that is less thanabout 500 μm, for example, less than about 100 μm, or even less thanabout 50 μm, e.g., as small as about 1 μm. For example, the spot sizecan have ranges from about 1 μm to about 50 μm, from about 50 μm toabout 100 μm, and from about 100 μm to about 500 μm. The spot size ofthe focal region can be determined, for example, in air. Such spot sizecan be selected as a balance between being small enough to provide ahigh fluence or intensity of EMR in the focal region (to effectivelyirradiate pigmented structures in the dermis), and being large enough tofacilitate irradiation of large regions/volumes of the skin tissue in areasonable treatment time.

A high NA optical system delivers different energy densities todifferent depths along an optical axis. For example, optical systemhaving an NA of about 0.5 focuses a radiation to about a 2 μm diameterfocal region width (i.e., waist) at focus. The focal region has afluence (i.e., energy density) at focus of about 1 J/cm². Because of thehigh NA (i.e., fast) optical system, at a location just 10 μm out offocus the radiation has an energy density of 0.03 J/cm² or 3% the energydensity at focus. The radiation a mere 30 μm out of focus has an energydensity that is just 0.4% (0.004)/cm²) of the in-focus energy density.This precipitous change in energy density along the optical axis allowsfor depth selective tissue treatment to be possible; but it alsorequires the precise depth positioning of the focal region (e.g., towithin tens of micrometers) within the target tissue.

The exemplary optical arrangement can also be configured to direct thefocal region of the EMR onto a location within the dermal tissue that isat a depth below the skin surface, such as in the range from about 30 μmto about 2000 μm (e.g., between about 150 μm to about 500 μm). Suchexemplary depth ranges can correspond to typical observed depths ofpigmented regions in skin that exhibit dermal melasma or other targetsof interest. This focal depth can correspond to a distance along theoptical axis between a lower surface of the apparatus configured tocontact the skin surface and the location of the focal region.Additionally, some embodiments can be configured for treating targetswithin the epidermis. For example, an optical arrangement may beconfigured to direct a focal region of the EMR to a location within theepidermis tissue (e.g., about 5 μm to about 2000 μm beneath the skinsurface). Still other embodiments may be configured for treating atarget deep in the dermis. For example, a tattoo artist typicallycalibrates his tattoo gun to penetrate the skin to a depth from about 1mm to about 2 mm beneath the skin surface. Accordingly, in someembodiments an optical arrangement may be configured to direct a focalregion of the EMR to a location within the dermis tissue in a range fromabout 0.4 mm to 2 mm beneath the skin surface.

It can be desirable that a treatment system for treatment of tissues becapable of identifying treatment areas in a target tissue. (e.g., byimaging: pigments, interface between dermal and epidermal layers in thetarget tissue, cell membranes, etc.). It can also be desirable tomonitor/detect the interaction between the EMR and the target tissue(e.g., plasma generation in tissue). Additionally, based on thedetection, the treatment system can modify the treatment process (e.g.,by changing intensity, size/location of focal region in the targettissue, etc.). Below, various embodiments of treatment systems aredescribed.

In order to further summarize, a table is presented below that includesparameter ranges for some exemplary embodiments.

Min. Nom. Max. Numerical Aperture 0.01 0.5 >1 Depth of Focal 0 250 5000Region (μm) Wavelength (nm) 200 1060 20,000 Rep. Rate (Hz) 10 10,000200,000 Pulse Duration (ns) 1 × 10⁻⁶ 100 1 × 10⁵ Pulse Energy (mJ) 0.012 10000 Average Power (W) 0.001 20 1000 M² 1 1.5 3 Laser OperationPulsed or Continuous Wave (CW) Scan Width (mm) 0.1 10 500 Scan Rate(mm/S) 0.1 250 5000 No. Scan Layers (-) 1 10 100 Scan Pattern FormRaster, Boustrophedon, Zig-Zag, Spiral, Random, etc.where depth of focal region is a depth within the tissue (e.g., depth offocal region=0 can be at about a surface of the tissue) and M² is aparameter characterizing a quality of the EMR beam.

Feedback Detection and EMR-Based Treatment

FIG. 5 is a schematic illustration of a treatment system 500. Thetreatment system 500 can include an optical system 502, an EMR detectionsystem 504 and a controller 506. The optical system 502 can includeoptical elements (e.g., one or more of mirrors, beam splitters,objectives, etc.) for directing EMR 510 generated by a source (e.g., alaser) to a focal region 552 of a target tissue 550. The EMR 510 caninclude an imaging radiation for imaging a dermal and/or epidermal layerof a target tissue 550 (e.g., skin). The EMR 510 can also include atreatment radiation for treatment of a region in the target tissue(e.g., region 522 of the target tissue 550). In some implementations,the EMR 510 can include only one of an imaging radiation and a treatmentradiation in a given time period. For example, EMR 510 can include thetreatment radiation for a first time duration and the imaging radiationfor a second time duration. In other implementations, the EMR 510 cansimultaneously include both the imaging and the treatment radiations ina given time period. According to some embodiments, the imagingradiation is of a wavelength generally equal to that of the treatmentradiation; and, the imaging radiation has a power less than thetreatment radiation. According to another embodiment, the imagingradiation is provided by an imaging radiation source other than thesource providing the treatment radiation, and the imaging radiation hasa wavelength different than the treatment radiation.

The EMR detection system 504 (e.g., photodiode, charged-coupled-device(CCD), spectrometer, photon multiplier tube, and the like) can detectsignal radiation 512 generated by the target tissue 550 due to itsinteraction with EMR 510 and/or a portion of EMR 510 reflected by thetarget tissue. For example, EMR 510 having an intensity above athreshold value (e.g., treatment radiation) can generate a plasma in thetarget tissue. The plasma can produce the signal radiation 512, forexample, due to its interaction with the EMR 510. The signal radiation512 can be representative of properties of the plasma (e.g., thepresence of plasma, the temperature of the plasma, the size of theplasma, components of the plasma, etc.)

In some implementations, EMR 510 having an intensity below the thresholdvalue (e.g., imaging radiation) can interact with the target tissuewithout significantly perturbing the target tissue 550 (e.g., withoutdamaging the target tissue 550, generating plasma in the target tissue550, etc.) The signal radiation 512 generated from such an interactioncan be used to image the target tissue 550 (e.g., portion of the targettissue 550 in the focal region of EMR 510). This signal radiation 512can be used to detect pigments in the target tissue 550 (e.g., pigmentslocated in the focal region of the target tissue). According to someembodiments, non-pigmented tissues are imaged. For example, as theimaging radiation (e.g., EMR 510) passes through cellular structureshaving different indices of refraction, the light is reflected as signalradiation 512.

The optical system 502 and the EMR detection system 504 can becommunicatively coupled to the controller 506. The controller 506 canvary the operating parameters of the treatment system 500 (e.g., bycontrolling the operation of the optical system 502). For example, thecontroller 506 can move the focal region 552 of the EMR 510 in thetarget tissue 550. As discussed in greater detail below, this can bedone, for example, by moving the optical system 502 relative to thetarget tissue 550, and/or by moving optical elements within the opticalsystem 502 (e.g., by controlling actuators coupled to the opticalelements) to vary the location of the focal region 552. The controller506 can receive data characterizing optical detection of signalradiation 512 from the EMR detection system 504.

The controller 506 may control the properties of the EMR 510. Forexample, the controller 506 can instruct the source of EMR 510 (e.g., alaser source) to change the properties (e.g., intensity, repetitionrate, energy per pulse, average power, etc.) of the EMR 510. In someimplementations, the controller 506 can vary the optical properties(e.g., location of focal region, beam size, etc.) of the EMR 510 byplacing/controlling an optical element (e.g., objective, diffractiveoptical element, etc.) in the path of the EMR. For example, thecontroller 506 can place an objective in the path of EMR 510 and/or movethe objective along the path of the EMR 510 to vary the size of thefocal region of the EMR 510.

The controller 506 can determine various characteristics of the targettissue 550 and/or interaction between the EMR 510 and the target tissue550 (e.g., plasma generation in the target tissue 550) based ondetection of the signal radiation 512 from the EMR detection system 504.In one implementation of the treatment system 500, the controller 506can determine one or more of a distribution of a pigment, a topographyof dermal-epidermal layer junction, etc., in the target tissue 550.Furthermore, the controller 506 can be configured to generate a mapindicative of the detected distribution of one or more of theaforementioned properties of the target tissue 550. Determination of thesuch distributions and/or generation of the distribution map can bereferred to herein as imaging.

In certain embodiments, the target tissue 550. For example, in aCartesian coordinate system, the target can be scanned along one or moreaxes (e.g., along the x-axis, the y-axis, the z-axis, or combinationsthereof). In alternative embodiments, scanning can be performedaccording to other coordinate systems (e.g., cylindrical coordinates,spherical coordinates, etc.). The scan can be performed using theimaging beam (e.g., EMR 510 having an intensity below a threshold value)and the signal radiation 512 corresponding to various regions in thetarget tissue 550 in the path of the imaging beam can be detected by theEMR detection system 504. Characteristics of the signal radiation 512(e.g., intensity) can vary based on the pigments in the portions of thetarget tissue 550 that interact with the imaging beam (e.g., pigments inthe focal region 552 of the imaging beam). The controller 506 canreceive a signal from the EMR detection system 504 that can include datacharacterizing the detected characteristic (e.g., intensity) of thesignal radiation 512. The controller 506 can analyze the received data(e.g., compare the received data with predetermined characteristicvalues of the detected signal radiation 512 in a database) to determinethe presence/properties of pigments in the target tissue 550.

In some implementations, the controller 506 can determine a location ofa portion of the target tissue 550 to be treated (“target treatmentregion”) based on the signal radiation 512. For example, it may bedesirable to treat a layer in a target tissue 550 (e.g., dermal layer ina skin tissue) located at a predetermined depth from the surface of thetarget tissue 550. The optical system 502 can be adjusted (e.g., bypositioning the optical system 502 at a desirable distance from thesurface of the target tissue 550) such that the focal region 552 isincident on the surface of the target tissue 550. This can be done, forexample, by scanning the optical system 502 along the z-direction untilthe signal radiation 512 exhibits predetermined characteristicsindicative of interaction between the EMR 510 and the surface of thetarget tissue 550. For example, an interface material (e.g., an opticalslab, a gel, etc.) can be placed on the surface of the target tissue550, and as the focal region 552 transitions from the target tissue 550to the interface material, the characteristic of the signal radiation512 can change. This can be indicative of the location of the focalregion 552 of the EMR 510 at or near the surface of the tissue. Once theoptical system 502 is positioned such that the focal region 552 of theEMR 510 is at or near the surface of the target tissue 550, the opticalsystem 502 can be translated (e.g., along the z-direction) such that thefocal region 552 is at the predetermined depth below the surface of thetarget tissue 550.

The controller 506 can vary the operating parameters of the treatmentsystem 500 based on the signal received from the EMR detection system504 including data characterizing the detected characteristic of thesignal radiation 512. For example, some embodiments of the EMR detectionsystem 504 can detect a depth of a dermis-epidermis (DE) junction in thetarget tissue 550, and the controller 506 can adjust a depth of thefocal region 552 in response to the depth of the DE junction. In thismanner, the DE junction can be employed as a reference for determiningthe depth of the focal region 552 within the dermis. Additionally, someembodiments of the EMR detection system 540 can quantify a proportion ofmelanin present in an epidermal layer of a skin (e.g., via use of aspectrophotometer). Based upon the proportion of melanin, the controller506 can suggest one or more changes in laser parameters to a designatedpersonnel (e.g., a clinician). According to some embodiments, changes inlaser parameters can include at least one of varying energy per pulseinversely with the proportion of melanin detected, increasing focusangle with an increase in the proportion of melanin, and modifying depthof the focal region 552 based upon the proportion of melanin.

In some implementations, an acoustic sensor 530 (e.g., acoustic sensor)can be coupled to the target tissue 550, and the acoustic sensor 530 candetect characteristics of interaction between EMR 510 and target tissue550. For example, an acoustic sensor can detect pressure waves 552generated by the creation of plasma in the target tissue 550 (e.g.,plasma generated in focal region 552). Examples of the acoustic sensor530 can include: piezoelectric transducers, capacitive transducers,ultrasonic transducers, Fabry-Perot interferometer, and piezo electricfilms.

In one aspect, the pressure waves 532 can be shock waves, a sharp changein pressure propagating through a medium (e.g., air) at a velocityfaster than the speed of sound in that medium. In another aspect, thepressure waves 532 can be acoustic waves that propagate through themedium at a velocity about equal to the speed of sound in that medium.

Photoacoustic imaging (optoacoustic imaging) is a biomedical imagingmodality based on the photoacoustic effect. In photoacoustic imaging,non-ionizing laser pulses are delivered into biological tissues (whenradio frequency pulses are used, the technology is referred to asthermoacoustic imaging). Some of the delivered energy will be absorbedand converted into heat, leading to transient thermoelastic expansionand thus wideband (i.e. MHz) ultrasonic emission.

Sensor measurement data from the acoustic sensor 530 can be transmittedto the controller 506. The controller 506 can use this data forvalidation of pigment detection via the signal radiation 512. Accordingto some embodiments, treatment is confirmed through the detection of theshock waves 532. Presence and/or intensity of pressure waves 532 iscorrelated to a plasma being generated and a plasma mediated treatmentbeing performed. Additionally, by mapping at which focal regionspressure waves 532 are detected, a comprehensive map of treated tissuemay be created and documented.

FIG. 6 is a diagram illustrating one exemplary embodiment of an opticalsystem 600. The optical system 600 can guide the EMR beam 602 from anEMR source 605 to a target tissue 650. The EMR source 605 can be a laser(e.g., a Q-smart 450 laser from Quantel that has a 450 mJ pulse energy,a 6 nanosecond [nS] pulse duration, and a wavelength of 1064 nm orharmonic of 1064 nm). According to some embodiments, an EMR beam 602 canbe introduced into the optical system 600 via an adapter 610. Theadapter can be configured to secure an EMR source that generates the EMRbeam 602 to an articulating arm e.g., arm 20 of mounting platform 12 ofFIG. 1.

According to some embodiments, a diffractive optical element (DOE) 620(e.g., beam splitters, multi-focus optics, etc.) can be placed in thepath of the EMR beam 602. The DOE 620 can alter the properties of theEMR beam 602 and transmit a second EMR beam 604. For example, the DOE620 can generate multiple sub-beams that are focused to different focalregions. Implementations and use DOE for treatment of target tissue arediscussed in greater detail in U.S. Provisional Application 62/656,639,entitled “Diffractive Optics For EMR-Based Tissue Treatment,” theentirety of which is incorporated by reference herein. The second EMRbeam 604 (e.g., multiple sub-beams generated by the DOE 620) transmittedby the DOE 620 can be directed toward the target tissue 650 by a beamsplitter 640 (e.g., a dichroic beam splitter). An example of a dichroicbeam splitter can include a short pass dichroic mirror/beam splitterthat has a cutoff wavelength of about 950 nm, a transmission bandbetween about 420 nm to about 900 nm, and a reflection band betweenabout 990 to about 1600 nm (Thorlabs PN DMSP950R). The second EMR beam604 can be reflected by the beam splitter 640, and directed to anobjective 660. The objective 660 can focus the EMR beam 604 to a focalregion 652 in the target tissue 650 via the window 645. An example ofthe objective 662 is an Edmunds Optics PN 67-259 aspheric lens having adiameter of about 25 millimeters (mm), a numerical aperture (NA) ofabout 0.83, a near infrared (NIR) coating, and an effective focal lengthof about 15 mm. The window 645 can be used to hold the target tissue 650in place.

In some implementations, the EMR beams 602, 604 can be expanded by abeam expander (not shown) placed in the path of the EMR beams 602, 604.Beam expansion can allow for a desirable NA value of the optical system600. For example, a laser beam generated by a Q-smart 450 laser can havea beam diameter of about 6.5 mm and can require a beam expander that canexpand the laser beam to twice the diameter. The expanded EMR beams 602,604 can be focused using an approximately 15 mm EFL lens to focus theEMR beams 602, 604 with a sufficiently high NA (e.g., greater than 0.3).

The optical system 600 can be arranged such that the focal region 652 ofthe EMR beam 604 is located below the epidermis of the target tissue650. This can be done, for example, by moving the optical system 600relative to the target tissue 650 and/or moving the objective 660 alongthe beam path of the EMR 604. In one implementation, a position of theoptical system 600/optical elements in the optical system 600 can bemoved by a controller (e.g., controller 506). Placing the focal region652 below the epidermis (e.g., below the dermis-epidermis (DE) junction)can reduce or substantially inhibit undesirable heat generation in theepidermis, which can lead to hyperpigmentation or hypopigmentation ofthe epidermis. This can also allow for targeting of regions in thedermis for heat and/or plasma generation.

Interaction between the second EMR beam 604 and the target tissue 650can lead to the generation of signal radiation 606. As described above,signal radiation 606 can include radiation generated by plasma in thetarget tissue 650 (“tissue radiation”). Tissue radiation can havewavelengths that lie in the transmission band of the beam splitter 640.As a result, tissue radiation can be largely transmitted by the beamsplitter 640. The signal radiation 606 can also include radiation havinga wavelength similar to that of the second EMR beam 604 (“systemradiation”). The wavelength of the system radiation can lie in thereflection band of the beam splitter 640. As a result, a small portion(e.g., 10%) of the system radiation is transmitted by the beam splitter640.

Signal radiation 608 transmitted by the beam splitter 640 can includeboth tissue radiation and system radiation (or a portion thereof).Portions of the signal radiation 608 can be captured by EMR detector690. The EMR detector 690 can communicate data characterizing thedetection of signal radiation 608 (or a portion thereof) to a controller(e.g., controller 506). The controller can, for example, based on thedetection (e.g., intensity of the transmitted signal radiation 608)alter the operation of the source 605 (e.g., switch off the source 605).

In one implementation, the optical system 600 can be used as a confocalmicroscope. This can be done, for example, by placing a second objective(not shown) upstream from the aperture 680. The aperture can reimage thesignal radiation 606 by focusing at a focal plane that includes theaperture 680. The aperture 680 can filter (e.g., block) undesirablespatial frequencies of the signal radiation 608. This configuration canallow for filtering of signal radiation associated with differentregions in the target tissue 650 (e.g., regions of target tissue atdifferent depths relative to tissue surface 654). By changing thedistance between the imaging aperture 680 and the target tissue 650(e.g., by moving imaging aperture 680 along the path of signal radiation608), different depths of the target tissue can be imaged. In someimplementations, a controller (e.g., controller 506) can move theimaging aperture 680 by transmitting commands to an actuator. Thecontroller 506 can analyze the detection data and determine the presenceof plasma in the target tissue 650, distribution of pigments in thetarget tissue, and the like. The optical system 600 can be used todetect damage in the window 645. The damage to the window 645 can becaused by interaction between the second EMR beam 604 and the window 645(e.g., when the intensity of the EMR beam is high, prolonged interactionwith the EMR beam 604, etc.). Detection of damage in the window 645 canbe implemented by determining a change in intensity in the signalradiation resulting from damage in the window 645. This can be done, forexample, by positioning the focal region 652 incident on the window 645(e.g., near the surface of the window 645, at the surface of the window645, within the window 645) and detecting an intensity of the signalradiation 606 (e.g., by using a photodetector as the EMR detector 690).This intensity can be compared with an intensity previously measuredwhen the focal region 652 is located on comparable location of anundamaged window 645. Based on this comparison damage in the window 645can be determined.

FIG. 7 is an illustration of an embodiment of an optical system 700. Theoptical system 700 can include a microscope attachment 770 having aneyepiece 790. The microscope attachment 770 can capture signal radiation608 (or a portion thereof) transmitted by beam splitter 640. The signalradiation 608 can be reimaged by a tube lens 750 (e.g., Edmunds OpticsPN 49-665 25 mm Diameter×50 mm EFL aspherized achromatic lens). The tubelens 750 can reimage the signal radiation 608 to a pupil plane 720 ofthe eyepiece 790 (e.g., Edmunds Optics PN 35-689 10X DIN eyepiece).

As described above, the signal radiation 608 can include both tissueradiation and system radiation. Due to difference in their wavelengths,images of the tissue radiation and system radiation are generated atdifferent locations (e.g., at different planes). As a result, if theeyepiece 790 is positioned to capture the image generated by systemradiation, it may not be able to accurately capture the image associatedwith tissue radiation. However, the eyepiece 790 can be calibrated tocapture signal radiation having a different wavelength than the systemradiation at the focal region of the system radiation. One way ofcalibrating is by using a material having an index of refraction similarto that of the target tissue 650 as a phantom (e.g., acrylic).Calibrating the eyepiece 790 can include focusing the second EMR beam604 into the phantom (e.g., by objective 660) and inducing a breakdown(e.g., laser induced optical breakdown) at the focal region of thesecond EMR beam 604. This can be followed by impinging the second EMRradiation having a predetermined wavelength onto the phantom (e.g. at anoblique angle) and measuring the intensity of EMR radiation having thepredetermined wavelength at the eyepiece 790. The axial location of theeyepiece 790 can be adjusted (e.g., along the z-axis) to maximize theintensity of detected radiation from the second EMR source. In certainembodiments, a sensor can be used instead of the eyepiece 790. Examplesof sensors can include CMOS and CCD imagers. The sensor generates adigital image in response to radiation at a sensor plane. The digitalimage represents an image of the focal region 652.

FIG. 8 is an illustration of an embodiment of an optical system 800having a fiber coupler attachment 802. The fiber coupler attachment 802includes a lens tube 810 that can image light from the objective 660 andbeam splitter 640 as described above. The lens tube 810 can focus thesignal radiation 608 at a pupil plane 815 (e.g., plane parallel to thex-y axis and including the collimating lens 820). The focused signalradiation 608 can be collimated to a desirable size using thecollimating lens 820, and can be directed to a coupling lens 830. Thecoupling lens 830 can focus the signal radiation 608 with an NA which isdesirable for coupling into a fiber attached to a fiber connector 840.The fiber can be optically connected to one or more EMR detectors (e.g.,detector 504). According to some embodiments, the coupler attachment 802can further include an imaging aperture 850 located at the pupil plane815. The aperture can filter portions of the signal radiation 608 thatare not emanating from the focal region 652. According to someembodiments, a detection instrument (e.g., photodiode, spectrometer,etc.) may be placed directly after the imaging aperture 850 without afiber optic or related optics. Calibration of the imaging aperture 850relative the lens tube 810 may be achieved in a process similar to thatdescribed above in reference to calibration of the eyepiece 790.

Feedback detection can be used in conjunction with EMR-based treatmentin many ways. Exemplary applications are described below to demonstratesome ways feedback informed EMR-treatment may be practiced. Broadlyspeaking, the examples described below may be categorized into threespecies of feedback informed EMR-treatment. These three speciesencompass examples that 1.) detect plasma; 2.) reference a focal regionposition; and 3.) image a tissue. These three categories of use are notintended to be an exhaustive (or mutually exclusive) list ofapplications for feedback informed EMR-based treatment.

PLASMA FEEDBACK EXAMPLES

Some treatments include the formation of a plasma during treatment(e.g., thermionic plasma or optical breakdown). In some embodiments,properties of a detected plasma are indicative of potentialeffectiveness of treatment. For example, in treating a dermal pigmentcondition a focal region is located deep within the skin, so that itwill coincide with dermal pigment as it is scanned during treatment. Asthe focal region is scanned over the skin, a laser source delivers apulsed laser, such that where the focal region and dermal pigmentcoincide thermionic plasma is formed. The formation of the thermionicplasma is indicative that 1.) a pigment is present within the skin, 2.)the pigment at a moment of plasma formation is collocated with the focalregion (e.g., X-Y coordinates, as well as depth), and 3.) the pigment atthis location has been treated (e.g., the pigment has been disrupted).

In other circumstances, plasma formation can indicate a need for systemmaintenance. For example, some systems include a window that is placedin contact with a tissue undergoing treatment. The window can serve manyfunctions including: contact cooling, stabilizing the tissue, providinga depth reference for the tissue, and evacuating blood or other fluidsfrom the tissue through pressure. Radiation (e.g., laser beam) alsopasses through the window for treatment of a treatment region below. Insome cases, the radiation can cause breakdown within the window or at asurface of the window, resulting in plasma generation and windowetching. If the system continues to deliver radiation after plasmageneration at the window, burning or thermal damage of the tissuedirectly in contact with the window often results.

FIG. 9 illustrates a flow chart for a plasma detection method 900 duringradiation-based tissue treatment, according to some embodiments. First,a surface of a tissue is contacted using a window 906. The windowcontacts an outer surface of the tissue. The window is configured totransmit the transmit a treatment radiation. Typically, the windowprovides a datum surface, such that placing the surface of the tissue incontact with the window effectively references the outer surface of thetissue. According to some embodiments, the window provides additionalfunctions including, but not limited to, preventing movement of thetissue during treatment, contact cooling of the tissue being treated,and evacuation of blood (or other competing chromophores) within thetissue through compression.

A treatment radiation is then generated 908. The treatment radiation istypically generated by a radiation source. The treatment radiation isconfigured to produce an effect in the tissue, which can result in animproved or desired change in appearance. In certain embodiments, tissueeffects can be cosmetic. In other embodiments, tissue effects can betherapeutic. According to some embodiments, the tissue effect includesgeneration of selective thermionic plasma in presence of a chromophore.Parameter selection for a treatment radiation is dependent on thetreatment being performed as well as the tissue type and individualpatient. Details related to treatment radiation generation 900 andrelevant parameter selection to produce an effect in tissue (e.g., acosmetic effect) are described in detail above.

The treatment radiation is focused to a focal region 910. Typically, thetreatment radiation is focused 910 by a focus optic. According to someembodiments, the focal region has a width that is smaller than about 1mm, about 0.1 mm, about 0.01 mm, or about 0.001 mm. The focal region maybe positioned at a first region. In some embodiments, the first regionis located within the tissue specifically at a location to be treated.In some cases, the first region may be intentionally or unintentionallylocated outside of the tissue, for example within the window that is incontact with the tissue.

The focal region is scanned 912, typically by a scanning system (e.g.,scanner). Examples of scanning include: tipping/tilting the focalregion, rotating the focal region, and translating the focal region.Further description of relevant scanning means is described in U.S.patent application Ser. No. 16/219,809 “Electromagnetic Radiation BeamScanning System and Method,” to Dresser et al., incorporated herein byreference in its entirety. According to some embodiments, the treatmentradiation is pulsed, such that approximately no treatment radiation isdelivered as the focal region is scanned (e.g., moved for the firstregion to a second region). The focal region may also be scannedcontinuously. In this case, timing of treatment radiation pulses andscan parameters control the locations for the first region and thesecond region.

A plasma is generated by the treatment radiation 914. The plasma istypically generated within or near the focal region, because fluence isat a maximum within the focal region. According to some embodiments,plasma is generated 914 selectively a pigmented region throughthermionic-plasma generation. Alternatively, the plasma may be generated914 through non-selective laser induced optical breakdown.

The plasma is then detected 916. A detector typically detects a signalradiation emanating from the plasma 916. Examples of signal radiationdetection include: optical detection, acoustic detection, spectroscopicdetection of laser induced breakdown (e.g., laser induced breakdownspectroscopy), plasma generated shockwave (PGSW) detection, plasmaluminescence detection, plasma (plume) shielding detection, and plasmaphotography. In some embodiments, properties of the plasma aredetermined based upon the detection of the plasma 916. Examples ofproperties of the plasma include: presence of plasma, intensity ofplasma, spectral content of plasma, and position of plasma. According tosome embodiments, a property of the signal radiation is recorded andstored, for example by the controller.

In some embodiments, it is determined if the plasma is located at leastpartially within the window 918, based upon the detected plasma. Forexample, in some embodiments an optical signal radiation including aspectral component known to be representative of a material in thewindow and not in the tissue may be detected indicating that the plasmais partially within the window. In another version, intensity of anoptical signal radiation may reach exceed a known threshold implyingthat the plasma is at least partially within the window.

Parameters related to the treatment radiation are controlled 920 basedin part upon the detected plasma (e.g., the determination 918 that theplasma is or is not partially located in the window). Examples ofparameters related to the treatment radiation can include, but are notlimited to, an energy per pulse, a repetition rate, a position of thefocal region, or a size of the focal region. These treatment radiationparameters can be employed alone or in combination with one another orother treatment radiation parameters without limit. For example, thedetermination that the plasma is partially located in the window may beused as a triggering event to cease the treatment radiation.

In some embodiments, a map is generated that can include a matrix ofproperties mapped to location, for example by the controller. As anexample, the map may include: a first property of a first signalradiation emanating from a first plasma at a first location can bemapped to a coordinate for the first location, and a second property ofa second signal radiation emanating from a second plasma at secondlocation mapped to a coordinate for the second location. An exemplarymap can include a four-dimensional matrix having three orthogonal axesrelated to the position of the focal region, and a fourth axes relatedto one or more properties of the plasma. In some versions, the map maybe used as an indication of individual treatment effectiveness. A systemsuitable for performing the above described plasma detection method isdescribed in detail below

Referring to FIG. 10, schematics are shown for a plasma detection andtreatment system 1000, according to some embodiments. In someembodiments, a window 1006 is configured to contact a surface of atissue 1008, for example an outer surface of the tissue 1008. The window1006 includes an optical material configured to transmit the EMR beam,for example: glass, a transparent polymer (e.g., polycarbonate), quartz,sapphire, diamond, zinc-selenide, or zinc-sulfide.

The imaging and treatment system 1000 includes a focus optic 1010. Thefocus optic 1010 (e.g., objective) is configured to focus anelectromagnetic radiation (EMR) beam 1011 and generate a plasma 1012within the tissue 1008. The plasma may be generated selectively at achromophore within the tissue 1008 through thermionic generation. Inother embodiments, the plasma 1012 is non-selectively generated throughoptical breakdown. The EMR beam 1011 may be generated using a radiationsource (not shown). The EMR beam 1011 may include any of collimated ornon-collimated light and coherent and non-coherent light.

A detector 1014 is configured to detect the plasma 1012. Examples ofplasma detectors 1014 include: photosensors, for example photodiodes andimage sensors; acoustic sensors, for examples surface acoustic wavesensors, piezoelectric films, vibrometers, and etalons; and, morespecialized detectors, for example spectrometers, spectrophotometers,and plasma luminance (or shielding) optical probes.

In the shown embodiment, the plasma detector includes a photodetector(e.g., a photodiode), which senses visible light 1016 (e.g., signalradiation) emanating from the plasma 1012. According to someembodiments, a tube lens 1018 is used in conjunction with the focusoptic 1010 to direct and focus the visible light 1016 incident thedetector 1014. The detector 1014 is communicative with a controller1015, such that data associated with the detected plasma is input to thecontroller 1015.

A scanner 1022 is configured to scan a focal region of the EMR beam1011. The scanner typically scans the focal region in at least onedimension. And, in some embodiments, the scanner 1022 scans the focalregion in all three dimensions. Referring to FIG. 10, the scanner 1022is shown scanning the focal region left to right from a first region1024 to a second region 1026 of the tissue 1008.

As the scanner 1022 scans the focal region, the EMR beam 1011 can bepulsed, causing a first plasma to be generated at the first region 1024and then a second plasma to be generated at the second region 1026. Thefirst plasma and the second plasma are both detected by the detector1014. In some embodiments, data associated with the first detectedplasma and the second detected plasma are input to the controller 1015.In some embodiments, the data associated with one or more plasma eventsare used by the controller to control parameters associated with atleast one of the EMR beam 1011 and the scanner 1022.

According to some embodiments, the controller 1015 is configured tocontrol the EMR beam 1011 (e.g., terminate the EMR beam 1011) based upona determination if the plasma 1012 is located at least partially withinthe window 1008. In some versions, the controller 1015 determines if theplasma 1012 is at least partially located within the window 1006 basedupon an intensity of the signal radiation 1016 emanating from the plasma1012. The intensity of the signal radiation 1016 may be detected using aphotosensor (e.g., photodiode). According to another version, thecontroller 1015 determines if the plasma 1012 is at least partiallylocated within the window 1006 based upon a spectral component of thesignal radiation 1016. For example, according to some embodiments thewindow 1006 can include sapphire, which includes aluminum. A spectrapeak corresponding to aluminum is centered at about 396 nm. Skin doesnot normally contain aluminum. Therefore, if the signal radiation (takena precise time after a laser pulse [e.g., 10 μs]) includes a spectralpeak centered at about 396 nm it is likely that the plasma 1012 is atleast partially located within the window 1006. According to someembodiments, a spectral filter (e.g., notch filter) and a photosensor isused to detect the spectral content of the signal radiation. Accordingto other embodiments, a spectrometer or spectrophotometer is used todetect the spectral content of the signal radiation.

The controller 1015 may be configured to record one or more detectedproperties of the plasma 1012. In some embodiments, the controller 1015is configured to record a matrix (or map) of detected properties of theplasma 1012. For example, the controller 1015 may be configured to:record a first property of a first signal radiation emanating from afirst plasma 1012 at a first location 1024; map the first property to acoordinate for the first location 1024; record a second property of asecond signal radiation emanating from a second plasma at a secondlocation 1026; and map the second property to a coordinate for thesecond location 1026.

Individual embodiments are provided below to further explain plasmadetection in an EMR treatment device.

Plasma Feedback Example 1

A first plasma feedback example describes an in vitro study, whichquantifies changes in relative plasma light intensity demonstratingplasma presence. The in vitro study is performed with skin from a femaleYucatan pig, selected for its dark skin. A 10 W Nufern fiber laserhaving a wavelength of about 1060 nm is used as a laser source in the invitro study.

FIG. 11A is a schematic illustration of a treatment optical system 1100used in the in vitro study. The treatment optical system 1100 includes abeam combiner 1110 configured to receive a collimated laser beam 1112.The beam combiner 1110 includes a reflector 1114 that reflects theincident laser beam 1112. The reflector 1114 is selected to reflectlight having a predetermined wavelength range. In the current in vitrostudy, the laser beam 1112 has a wavelength of 1060 nm, and thereflector is a Thorlabs NB1-K14, which is 99.5% reflective over awavelengths range of 1047 to 1064 nm. The reflected laser beam 1112 isimaged and focused by a focus optic 1116. The focus optic 1116 used inthe in vitro study is a Thorlabs C240TME-C, which is an aspheric lenscapable of diffraction limited performance having an NA of 0.5 and aneffective focal length of 8 mm. The laser beam 1112 is focused to awaist (e.g., focal volume) in a skin sample 1118. At the waist of thelaser beam 1112, a plasma plume 1120 is generated within the skin sample1118. Radiation 1124 generated from the plasma plume 1120 is imaged bythe focus optic 1116 and is transmitted through the reflector 1114.After transmission through the reflector 1114, the radiation 1124 isimaged into a first end of a fiber optic (not shown) by a fiber coupler,1122. The fiber coupler used in the in vitro study is a ThorlabsPAF-SMA-7-A. A second end of the fiber optic is coupled to aspectrometer (not shown) which is an Ocean Optics HR2000+ ES. In anotherimplementation of the in vitro study, a notch filter (not shown) isdisposed between the reflector 1114 and the fiber coupler 1122 to blockportions of the radiation 1124 having a wavelength similar to that ofthe laser beam 1112 from entering the fiber optic. The skin sample,1118, is mounted on motorized staging 1130. A working distance betweenthe skin sample 1118, and the focus optic 1116, is maintained to controla depth of the waist of the laser beam 1112 within the skin sample 1118.

In another implementation of the in vitro study, a skin sample 1118having a melanin tattoo is placed on the motorized stage 1130 such thatthe waist of the laser beam 1112 is located about 0.2 mm deep into thesample 1118. The melanin pigment used in the melanin tattoo is fromCuttlefish ink (e.g., sepia ink). The melanin tattoo is locatedapproximately between a quarter of a millimeter and a millimeter deep inthe dermis of the skin sample. Depth of the tattoo pigment within theskin is verified by viewing a histological sample of the skin.

FIG. 11B illustrates a scan of a histological sample of the skin sample1118 having a melanin tattoo. The skin surface 1150 is shown at the topof the histology. An epidermis-dermis junction 1152 demarcates theepidermis and dermis layers of the skin. Melanin globules 1154 presentin the dermis constitute the melanin tattoo. The laser is operated at 20KHz, 100 ns pulse duration, and 0.5 mJ/pulse. The sample is scannedduring laser irradiation at a rate of 100 mm/s. The spectrometer isadjusted to capture light over a 5000 ms period and trigger thecapturing in response to the laser irradiation.

FIG. 12 illustrates spectra associated with radiation from melanintattoo and bare skin. The horizontal axis represents the wavelength ofthe radiation from the sample skin 1118 and the vertical axis representsthe relative intensity of the radiation. FIG. 12 illustrates a melanintattoo spectrum (e.g., centered at about 600 nm) and a bare skinspectrum generated when the skin 1118 is irradiated with a laser beam1112 (e.g., having a spectrum centered at about 1060 nm). The melanintattoo spectrum shows a measurement taken during irradiation of thesample at the location of the melanin tattoo (e.g., when waist/focalvolume of the input laser beam 1112 irradiates portions of the skinhaving melanin tattoo). The bare skin spectrum shows a measurement takenduring irradiation of a region of the sample skin 1118 that does notinclude the melanin tattoo. The melanin tattoo spectrum shows a presenceof a broad-spectrum light that includes radiation in the visiblespectrum (e.g., between 400 nm and 800 nm). The broad-spectrum lightindicates plasma formation during irradiation of the melanin tattoo. Thebare skin spectrum has generally no or very small visible spectrumcomponent. The lack of visible light component in the bare skin spectrumindicates that generally no plasma was formed during irradiation of thebare skin.

Another skin sample 1118 having a carbon tattoo (e.g., India ink) isplaced on the motorized stage 1130 beneath the focus optic 1116 suchthat the focus waist of the laser beam is located about 0.2 mm below thesurface of the skin sample 1118. The Carbon tattoo is locatedapproximately between a quarter of a millimeter and a millimeter deep inthe dermis of the skin sample 1118. The laser is operated at 20 KHz, 100ns pulse duration, and 0.5 mJ/pulse. The sample is scanned during laserirradiation at a rate of 100 mm/s. The spectrometer is adjusted tocapture light over a 5000 ms period and trigger capturing in response tothe laser irradiation.

FIG. 13 illustrates spectra associated with radiation from carbon tattooand bare skin. The horizontal axis represents the wavelength of theradiation from the sample skin 1118 and the vertical axis represents therelative intensity of the radiation. FIG. 13 illustrates a carbon tattoospectrum and a bare skin spectrum generated when the skin 1118 isirradiated with laser beam 1112. The carbon tattoo spectrum shows ameasurement taken during irradiation of the sample at the location ofthe carbon tattoo (e.g., when waist/focal volume of the input laser beam1112 irradiates portions of the skin having carbon tattoo). The bareskin spectrum shows a measurement taken during irradiation of a regionof the sample skin 1118 that does not include the carbon tattoo. Thecarbon tattoo spectrum shows a presence of a broad-spectrum light thatincludes radiation in the visible spectrum (e.g., between 400 nm and 800nm). The broad-spectrum light indicates plasma formation duringirradiation of the carbon tattoo. The bare skin spectrum has a generallyno visible spectrum component. The lack of light indicates thatgenerally no plasma was formed during irradiation of the bare skin.

It should be noted that the broad spectrum captured in the aboveexperiments results from the generation of plasma at many locations at arate of 20 KHz which is the repetition rate of the laser beam 1112. Anintegration time of the spectrometer is set at 1 ms or greater. Thisallows for characterization of the spectral information of plasmagenerated over multiple pulses of the laser beam 1112. After theinteraction between an incident laser pulse (of laser beam 1112) and theplasma, the plasma begins to cool and its electrons drop an energy levelthereby emitting light over narrow spectral bands. As the abovespectrometer measurements were integrated over multiple pulses it shouldbe understood that these narrow bands were not observable in thisexample. A second example is described below in which narrow spectralbands were detected.

Plasma Feedback Example 2

In the second example, narrow spectral bands of radiation 1124 generatedby plasma in the skin sample 1118 are experimentally observed. Theoptical system used for this detection is described in FIG. 11A. Theoptical system includes a fiber optic that allows for opticalcommunication between the optical system and an Ocean OpticsSpectrometer Model No. HR2000+ES. The optical system is opticallycommunicative with a Q-switch Nd:YAG laser (Quantel Q-Smart 450) with anarticulating arm such that a laser beam from the Q-switch Nd:YAG laseris directed into the system.

The skin sample 1118 is placed generally parallel to a focal region ofthe laser beam. The focal region is first placed just below a surface ofthe skin sample 1118. Multiple laser pulses were directed towards thesample skin 1118 with a spectrometer measurement being taken just aftereach laser pulse. Each laser pulse has sufficient peak power to producean optical breakdown resulting in the generation of a plasma in the skinsample 1118. Radiation 1124 from the plasma is captured, as described inreference to FIG. 11A, and communicated to the spectrometer.

FIG. 14 illustrates spectra of radiation 1124 generated by plasma in theskin sample 1118. Spectral results captured from the plasma after eachlaser pulse were averaged. The average spectra is shown in a chart 1400shown in FIG. 14. The chart 1400 has relative intensity in arbitraryunits along a vertical axis and wavelength in nanometers along ahorizontal axis. The averaged spectra includes spectral peaks at about589 nm and 766 nm. The averaged spectra also includes minor spectralpeaks at about 422 nm, about 455 nm, about 493 nm, about 521 nm, about553 nm, about 614 nm, and about 649 nm.

During the experiment, a sapphire window is placed between the skinsample 1118 and the focus optic 1116 in the path of the laser beam 1112.The laser beam 1112 is directed through the sapphire window into awaist/focal region located about 0.5 mm below the surface of the skin.FIG. 15 contains a chart 1500 that illustrates a radiation spectra froma plasma formed using a sapphire window in contact with the tissue. Thechart 1500 has relative intensity in arbitrary units along a verticalaxis and wavelength in nanometers along a horizontal axis. It can beseen in FIG. 15 that the major peaks at about 589 nm and about 766 nmare present. Additionally, an even larger peak is located at about 396nm. It has been discovered after the measurement that the sapphirewindow is damaged (e.g., etched) in a way consistent with a plasma beingformed within it. The 396 nm peak occurs repeatedly with the sapphirewindow present, only occurs when the sapphire window is present; and,the sapphire window appears damaged by plasma formation. Thisobservation indicates that this peak at about 396 nm can be used as anindicator of plasma formation within the sapphire window.

According to some embodiments, material components of a plasma aredetermined through spectral analysis and one or more parameters of laserbeam are adjusted based upon the material components of the plasma. Forexample, according to some embodiments a controller determines, from thespectral data, that a material other than that being treated is beingaffected by a plasma and adjusts laser parameters or deactivates a lasersource. Although, the second example uses a spectrometer for detectionof spectral content of the plasma, some embodiments determine spectralcontent of the plasma through alternative methods. For example, in someversions, a narrow band filter that passes only light centered about 396nm is placed over a photodiode, such that the photodiode detects lightonly at 396 nm. The photodiode is triggered to collect moments after(e.g., 100) after an EMR pulse. And, the controller is configured tostop firing the EMR source when the photodiode detects relatively highvalues, as relatively high values will only occur when the plasmaaffects the sapphire window.

Plasma Feedback Example 3

A third example demonstrates a plasma detection system that detectsplasma incorporated into an EMR-based treatment hand piece.

FIGS. 16A-16C illustrate drawings of according to the third example oftissue treatment and plasma detection. A tissue treatment and plasmadetection system 1600 is shown in FIGS. 16A-16C. FIG. 16A shows a frontview of the system 1600. FIG. 16B shows a cross-sectional view of thesystem 1600 taken along a B-B section line in FIG. 16A. And FIG. 16Cshows a detail view taken from within a C detail circle in FIG. 16B.

A fiber laser 1610 is configured to output a treatment radiation. Anexample of the fiber laser 1610 is a Feibo 1060 nm, 40 W, 20 kHz, fiberlaser from Feibo Laser Technologies Co., Ltd. Of Shanghai, China. Thetreatment radiation is directed by an optical system to a focus optic1620. An example focus optic is Thorlabs Part No.: A240. The focus optic1620 is configured to focus the treatment radiation through a window1622 to a focal region in a tissue (not shown). The optical system isconfigured to allow the focus optic 1620 to be scanned in all threedimensions. This subsequently causes the focal region of the treatmentradiation to be scanned in all three dimensions within the tissue.Scanning is achieved by three separate stages each responsible for asingle axis. An X-stage 1625 scans the focus optic in an X-axis. AY-stage 1626 mounted to the X-stage 1625 scans the focus optic in aY-axis. And, a Z-stage 1627 mounted to the Y-stage 1626 scans the focusoptic in a Z-axis (e.g., generally along an optical axis of the focusoptic). An exemplary X-stage is a Dover MMX 50 from Dover Motion ofBoxborough, Mass., USA, controlled with an Elmo DC whistle Goldcontroller from Elmo Motion Control Ltd. of Petach-Tikva, Israel. Anexemplary Y-stage is a Q545.140 stage controlled with E 873 controllerboth from Physik Instrumente L.P. of Auburn, Mass., USA. An exemplaryZ-stage is a New Scale 3M-FS from New Scale Technologies, Inc. ofVictor, N.Y., USA.

A printed circuit board (PCB) 1640 is adhered to the Z-stage 1627 andfaces the window 1622. The PCB 1640 contains a number of electroniccomponents and four photodiodes 1642. An example photodiode is an OsramCHIPLED part number SFH 2711 from OSRAM GmbH of Munich, Germany. Anotherexample photodiode is a Gallium Nitride Based sensor, GUVA-S125D fromRoithner Lasertechnik GmbH of Vienna Austria. Both example photodiodesmay be advantageous in some embodiments, because they are more sensitivedetecting light in ultra-violet (UV) and visible spectrum than innear-infrared (NIR). For this reason, these example photodiodes willdetect light from a plasma, but detect less reflected or scatteredtreatment radiation (e.g., 1060 nm laser light). In other embodiments,the photodiodes may be coated with an optical coating (e.g.,interference notch filter coating) to prevent detection of the treatmentwavelength. In still other embodiments, the photodiodes may be placedbehind a spectral filter (e.g., interference notch filter film) toprevent detection of the treatment wavelength.

Light from a plasma is converted into a small current by one or more ofthe photodiodes 1642. The current is converted into a voltage by atransimpedance amplifier. The voltage is then amplified by one or moreamplifiers and sampled by a microcontroller. The microcontroller samplesthe voltage using at least one of an analog to digital converter (ADC)and a comparator.

In some versions, a comparator compares the voltage to a threshold valueand triggers a timer (e.g., 32678 Hz) when the voltage exceeds thethreshold value. The microcontroller detects a plasma when the voltagestays above the threshold value for a defined duration (e.g., 3 ticks ofthe timer). In some embodiments, the threshold value is set high so thatplasma originating from treatment within the tissue will not exceed thethreshold value, but closer and brighter plasma originating from withinan optical window will. In this case, the plasma detector may be usedfor detecting unwanted plasma, such as plasma in the periphery tissue oroptical window, which may cause damage to the patient or the system.Once the plasma is detected, a signal can be sent to another controller(e.g., laser controller) that can log the plasma detection or altertreatments based upon the detection (e.g., stop treatment radiation).

According to some embodiments, the ADC may be used to detect plasmawithin the tissue (e.g., plasma consistent with treatment). The ADCassigns a digital value representative of plasma intensity based uponthe voltage from the one or more photodetectors. In some cases, thedigital value is logged along with current location values for one ormore of the X-stage 1625, the Y-stage 1626, and the Z-stage 1627. Inthis case, the logging of digital values relative focal region locationcan be formatted into a matrix (e.g., a map). The matrix may be used toindicate effectiveness of treatment or presence of chromophores withinthe tissue.

In some embodiments, presence of plasma at a first depth (e.g.,relatively shallow) can indicate damage to the system or an adverseevent; while, presence of plasma at a second depth (e.g., relativelydeep within the tissue) can indicate an effective treatment. It is,therefore, important in some embodiments, to ensure that a focal regionof the EMR beam is position at a desired focal depth.

FOCAL DEPTH REFERENCING EXAMPLES

As described in detail above, a depth of a focal region within a tissueneeds to be tightly controlled (e.g., +/−20 μm), in some embodiments.For example, treatment of dermal pigment requires a focal region beplaced at a depth approximately at the depth of the dermal pigmentwithin the tissue. If the focal region is too deep below the dermalpigment treatment will not be effective. If the focal region is tooshallow, melanocytes at the basal layer will be irradiated potentiallycausing an adverse event (e.g., hyperpigmentation or hypopigmentation).

Referring to FIG. 17, a flow chart 1700 is shown for a focal depthreferencing method 1700, according to some embodiments. First, anelectromagnetic radiation (EMR) beam is focused along an optical axis toa focal region 1710. In many cases, the EMR beam is generated by an EMRsource (e.g., laser). An optical window is disposed to intersect theoptical axis. In some versions, a surface of the window is substantiallyorthogonal to the optical axis. The EMR beam impinges upon at least onesurface of the optical window and a signal radiation is generated. Thesignal radiation in some embodiments includes a reflected portion of theEMR beam that is reflected at a surface of the window. In someembodiments, the window is configured to contact a tissue. The surfaceof the window may be understood optically as an optical interfacebetween a window material of the window and an adjacent materialproximal the surface of the window (e.g., air or tissue). In some cases,a difference in index of refraction between the window material and theadjacent material results in reflection of the reflected portion of theEMR beam. According to some embodiments, a signal radiation is generatedby scatter or transmission of a portion of the EMR beam at the window.

The signal radiation is detected 1712. According to some embodiments,the signal radiation is imaged by an imaging system. In some cases, animage of the signal radiation is formed at a sensor by the imagingsystem. Examples of sensors include photosensors and image sensors. Insome versions, a detector detects and measures an image width. Ingeneral, the image width will be proportionally related to a beam widthof the EMR beam incident the surface of the window. A magnification ofthe imaging system typically determines the proportionality of the imagewidth to a width of the EMR beam incident the window. According to someembodiments, the detector detects and measures an intensity of thesignal radiation.

Based upon the signal radiation, a reference focal position isdetermined 1714. For example, in some versions, the beam width of theEMR beam incident a surface of the window is measured, and a focalposition of the focal region is translated along the optical axis as thebeam width is measured. The reference position is found where the beamwidth is determined to be at a minimum. For another example, in someversions, an intensity of the signal radiation is detected as the focalposition of the focal region is translated along the optical axis. Inthis case, the reference position is found where a radiation signalintensity is found to be at a maximum.

Once the reference focal position is determined, the focal region istranslated to a treatment focal position 1716. Typically, the treatmentfocal position is a predetermined distance away from the reference focalposition along the optical axis. According to some embodiments, thefocal region is translated by moving an optical element (e.g.,objective) along the optical axis. In other embodiments, the focalregion is translated by adjusting a divergence of the EMR beam, forexample adjusting an optical power of an optical element. Eventually,the window is placed in contact with a target tissue resulting in thefocal region being positioned within the target tissue. According tosome embodiments, the target tissue is skin and the focal region ispositioned within a dermal tissue of the skin. Precise depth positioningof the focal region within tissue allows for treatment of previouslyuntreatable pigmentary conditions through thermionic-plasma or thermaldisruption. For example, the EMR beam can perform selectivethermionic-plasma mediated treatment of dermal pigmentary condition(e.g., dermal melasma) at a focal region located within the dermiswithout risking adverse irradiation of the epidermis.

Referring to FIG. 18B, in some embodiments, a second EMR beam 1816B isconfigured to be converged by the focus optic to a second focal region1818B located in the treatment position. In this case, the first EMRbeam 1816A may be configured only for referencing (e.g., by bringing afirst focal region 1818A incident upon the surface of window 1810 andthe second EMR beam 1816B may configured to achieve the desired effectin the tissue (e.g., a cosmetic effect). This may be advantageous inembodiments, where the tissue effect requires very high fluence (e.g.,10¹² W/cm²) and the window 1810 would likely be damaged if the first EMRbeam were to be used during referencing. According to some embodiments,the second EMR beam 1816B has a wavelength that approximately equal tothe first EMR beam 1816A. In other embodiments, the second EMR beam1816B has a wavelength that is different than that of the first EMR beam1816A. In this case, the treatment position may require calibrationbased upon differences in a focal length of the focus optic at the twodifferent wavelengths.

Referring to now FIGS. 18A-18B, schematics are shown for a focal depthreferencing and treatment system 1800, according to some embodiments.The focal depth referencing system 1800 includes a window 1810configured to contact a target tissue 1812. An optical system (e.g.,objective or focus optic) is configured to focus an electromagneticradiation (EMR) beam 1816 to a focal region 1818 along an optical axis1820. The optical axis 1820 intersects the window 1810. An opticaldetector 1822 is configured to detect a signal radiation 1824. Accordingto some embodiments, the signal radiation 1824 is generated by aninteraction between the EMR beam 1820 and the window 1810. In someversions, the interaction between the EMR beam 1820 and the window 1810is an interaction between a surface of the window 1810 and the EMR beam.The interaction between the EMR beam 1820 and the window 1810 typicallyis at least one of reflection, transmission, and scatter.

A controller 1826 is configured to take input from the optical detector1822 and translate a focal position of the focal region 1818 along theoptical axis 1820. Based at least in part upon feedback from the opticaldetector 1822, the controller 1826 determines a reference position 1828where a portion of the focal region 1818 is substantially coincidentwith a surface of the window 1810.

The signal radiation 1824 may emanate from a reflection of the EMR beam1816 incident the surface of the window 1810 and be imaged incident animage sensor 1822 using (in part) the focus optic 1814. According tosome embodiments, the controller 1826 determines the reference positionby determining a transverse width of the EMR beam 1816 that is incidentupon the surface of the window based upon the signal radiation; and,translating the focal region until the transverse width has a minimumvalue. According to another embodiment, the signal radiation emanatesfrom a reflection of the EMR beam 1816 at a surface of the window 1810and the detector 1822 is configured to detect an intensity of the signalradiation. In this case the controller may determine the referenceposition by translating focal region until the intensity of the signalradiation has a maximum value.

Finally, the controller 1826 translates the focal region 1818 to atreatment position a predetermined distance 1830 from the referenceposition 1828. In general, translating the focal region 1818 away fromthe reference position 1828 is done in a positive direction along theoptical axis 1820 (i.e., away from the optical system 1814). In someembodiments, the treatment position is configured to be located within atissue. For example, the predetermined distance can be configured tolocate the treatment position within a dermal tissue in skin. A stage1832 can be used to translate one or more optical elements (e.g., thefocus optic) in order to translate the focal region. The EMR beam 1816typically is configured to perform an effect in tissue (e.g., a cosmeticeffect) at or near the focal region located in the treatment position.An example tissue effect is selective thermionic plasma-mediatedtreatment of the tissue 1812.

In some embodiments, a second EMR beam is configured to be converged bythe focus optic to a second focal region located in the treatmentposition. In this case the first EMR beam may be configured only forreferencing and the second EMR beam may configured to perform the tissueeffect. This may be advantageous in embodiments, where the tissue effectrequires very high fluence (e.g., 10¹² W/cm²) and the window 1810 wouldlikely be damaged during referencing. According to some embodiments, thesecond EMR beam has a wavelength that is identical to the first EMRbeam. In other embodiments, the second EMR beam has a wavelength that isdifferent than that of the first EMR beam. In this case, the treatmentposition will need to be calibrated based upon differences in a focallength of the focus optic at the two different wavelengths. In someembodiments, a window referencing and treatment system 1800 is used tomeasure more than one reference position 1828.

For example, according to some embodiments, the window referencing andtreatment system 1800 also includes a scanning system. The scanningsystem is configured to move the focal region 1818 and optical axis 1820in at least one scan axis. In some cases, the scan axes can be generallyperpendicular to the optical axis 1820.

A parallelism measurement between the window and a scan axis can bedetermined by way of multiple reference position 1828 measurements atmultiple scan locations. For example, the referencing system 1800 isfirst used to determine a first reference position at a first scanlocation. Then, the scanning system relocates the optical axis 1818 to asecond scan location a distance along the scan axis from the first scanlocation. The referencing system 1800 then determines a second referenceposition. A difference between the first and second reference positionsdivided by the distance along the scan axis indicates a slope ofnon-parallelism between the window and the scan axis. Individualembodiments are provided below to further explain focal depthreferencing in an EMR treatment device.

Focal Depth Referencing Example 1

A first focal depth referencing example is described below. The firstfocal depth referencing example employs a feedback system such as aconfocal microscope. This configuration is advantageous in someembodiments as it can be used to reference surfaces within a tissue aswell as external tissue surfaces and window surfaces. For example,according to some embodiments, a focal region is referenced relative adermal-epidermal (DE) junction within the skin. This is achievable insome embodiments because of an index of refraction difference betweenthe epidermis (or melanin in a basal layer of the epidermis) and thedermis.

FIG. 19 illustrates a bench prototype 1900 for confocal imaging andplasma mediated therapy. A collimated laser beam 1901 enters theprototype 1900 through an entrance aperture 1902 and is projected upon areflector 1904. The reflector 1904 folds the laser beam 1901 toward anobjective 1906. The objective 1906 focuses the laser beam 1901 to afocal region 1907. The focused laser beam 1901 is directed toward asample holder 1908. The sample holder 1908 includes a window 1910, and asample located optically downstream from the window 1910. The sampleshown in FIG. 19 is skin that includes an epidermis 1912 and a dermis1914 located optically downstream from the epidermis 1912. A compliantmaterial, such as foam 1916, is used to press the sample against thewindow 1910 and the window against a landing of the sample holder 1908.The sample holder sits atop an X-Y stage 1918X and 1918Y. The prototype1900 scans the sample relative the laser beam. A Z-stage 1920 allows adistance between the objective 1906 and the sample holder 1908 to beadjusted. A micrometer screw gauge allows for tightly controlledmovement of the Z-stage 1920. The objective 1906 collimates a returnedlight 1922 from the focal region 1907. The radiation 1922 is at leastpartially transmitted through the reflector 1904. According to someembodiments, radiation 1922 passes through a filter 1923 (e.g. a notchfilter) such that only portions of the radiation 1922 having a certainwavelength range are accepted. The radiation 1922 is focused by a tubelens 1924 to an aperture 1926. The aperture 1926 is sized to accept onlyrays of light originating from focus 1907 (e.g., less than 50 μm).Finally, the radiation 1922 is projected upon a photodiode 1928.

In one implementation, the optical system 1900 is used as a confocalmicroscope. This can be done, for example, by placing the secondobjective 1924 upstream from the aperture 1926. The aperture 1926 canreimage the signal radiation 1922 by focusing the signal radiation at afocal plane that includes the aperture 1926. The aperture 1926 canfilter (e.g., block) undesirable spatial frequencies of the signalradiation 1922. This configuration can allow for filtering of signalradiation associated with different regions in the target tissue 1912and 1914 (e.g., regions of target tissue at different depths relative totissue surface). By changing the distance between the imaging aperture1926 and the target tissue 1912 and 1914 (e.g., by moving imagingaperture 1926 along the path of signal radiation 1922), different depthsof the target tissue can be imaged 1926 by transmitting commands to anactuator. The controller 506 can analyze the detection data anddetermine the presence of plasma in the target tissue 1912 and 1914,distribution of pigments in the target tissue, and the like.

Focusing a laser beam at a prescribed depth below a surface requiresprecise placement of the focal region 1907 relative to the surface. Itis therefore advantageous in some embodiments, to determine the locationof the objective 1916 relative the surface of the sample (e.g., surfaceof the sample facing the objective 1906). This can be done byreferencing the focal region 1907 with the surface of the sample. Usingthe bench prototype as described above, a test is performed to determinewhere the focal region is located with respect to the top and bottomsurface of the window 1910 as well as to a top surface of a porcine skinsample.

A Nufern 30 W fiber laser operating at a wavelength of 1060 nm is usedto provide the laser beam 1901 that has a diameter of about 7.5 mm. Thereflector 1904 is a dichroic mirror which reflects more than 90% of thelaser beam 1901 and transmits less than 10% at 1060 nm wavelength. Theobjective has an effective focal length of about 8 mm. The lens tube1924 focuses the returned light 1922 with an effective focal length ofabout 30 mm. The aperture 1926 is about 30 micrometers wide. The fiberlaser is operated at a power level of 0.1% (1 mJ/pulse) and a repetitionrate of 30 KHz. A signal from the photodiode 1928 is displayed upon anoscilloscope. When the fiber laser is turned on, the Z-stage 1920 isslowly scanned until a maximum signal is captured by the oscilloscope.

FIG. 20 illustrates a maximum radiation intensity measurement. Intensityis shown along a vertical axis in arbitrary units and time is shownalong a horizontal axis. The maximum radiation intensity signal 2002 isgenerated when the focal region 1907 is collocated on the top surface ofthe window 1910. The Z-stage 1920 micrometer reported a relativeposition of 0.487 mm where the maximum signal 2002 is observed. Nodetectable signal is observed at relative Z-stage positions of 0.458 mmand 0.519 mm.

In the above example, the position of the focal region was referenced ata window interface where reflection at the interface was found to begreatest. A difference in the index of refraction between materialscauses reflection at an interface between the two materials (e.g., airand the window). Reflection arising from a mismatch of index ofrefraction is sometimes understood as Fresnel reflection. Fresnelreflection varies with angle of incidence and light polarization. Forsimplicity, Fresnel reflection at a normal angle of incidence (whichdoes not depend on polarization) will be shown as an example. A normalFresnel reflection arising at a boundary between to materials havingdifferent indices of refraction will generally act according to:

$R = {\frac{n_{1} - n_{2}}{n_{1} + n_{2}}}^{2}$

where R is reflectance (proportion of light reflected), n₁ is index ofrefraction of a first material, and n₂ is index of refraction of asecond material. A good example of Fresnel reflection is provided bydiamond. A diamond has a very high index of refraction (e.g., 2.42). Airhas an index of refraction of unity (e.g., 1.00). Fresnel reflectance oflight normal to an air-diamond interface is approximately 17%. Fresnelreflectance tends to be at a minimum at a perpendicular angle andincreases at grazing angles. So, for a diamond, nearly ⅕ of the light isreflected at the air diamond interface, at a minimum. The result is thata diamond sparkles in light.

Within skin, melanin has a different index of refraction different thanthe surrounding tissue at optical wavelengths (e.g., melanin's index ofrefraction at 1064 nm is about 1.78 and the epidermal index ofrefraction is about 1.35). Therefore, normal Fresnel reflectance isabout 2% at a skin-melanin interface. A basal layer at the bottom of theepidermis contains melanocytes and is therefore very melanin rich. Justbelow the basal layer the dermis is typically free from melanin, exceptin pathological cases (notably dermal melasma). Therefore, in someembodiments the focal region is referenced with a dermal-epidermaljunction (e.g., basal layer) of the skin.

Focal Depth Referencing Example 2

A second focal depth referencing example uses a camera sensor instead ofan imaging (e.g., confocal) aperture. FIGS. 21A-21C illustrate anexample according to some embodiments. FIG. 21A shows a treatment system2100 configured to direct and focus a radiation (e.g., laser) into atarget tissue. The radiation beam is provided by a fiber optic 2110 andcollimated by a collimator 2112. The radiation beam is focused anddirected through the system 2100 by an optical system. The focusedradiation beam is ultimately directed out of a window 2114 at the bottomof the system 2100. The window 2114 is configured to contact a treatmenttissue, such that a focal region of the focusing radiation beam islocated within the target tissue. The system 2100 also includes a port2116. The port allows at least some portion of radiation from near thefocal region to be directed out it. The port 2116 therefore allows forsignal radiation from near the focal region to be “picked off” anddetected. One use for the signal radiation is focal depth referencing todetermine a reference focal position that corresponds with a partiallyreflective interface (e.g., a surface of the window 2114).

FIGS. 21B-21C illustrate the system 2100 having a removable referencingsystem 2120 attached to the port 2116. According to an exemplary use ofthe system 2100, the removable referencing system 2120 is installedprior to treatment and can be used to reliably locate the focal regionrelative a known reference (e.g., a tissue surface or a window surface).Referring to FIG. 21C, a signal radiation 2129 propagates generallyalong an optical axis 2130. Abeam splitter 2132 allows at least aportion of the signal radiation 2129 to transmit toward the windowreferencing system 2120. According to some embodiments, the beamsplitter substantially reflects the collimated radiation beam 2134,which is output from the collimator 2112. The signal radiation is imagedby an imaging lens 2136 (e.g., Edmund Optics PN: 33-020) onto a camerasensor 2138 (Mightex PN: SCE-B013-U). Measurements taken with the secondfocal depth referencing example system are provided below to demonstrateaccuracy and usefulness of the system.

The measurements represent a position of an objective lens along anoptical axis that results in a corresponding focal region beingcollocated with a surface of a window. Collocation of the focal regionand the surface of the window was determined by a participant taking themeasurement. The participant was responsible for determining theobjective lens position that causes an image of the signal radiation tohave a minimum size. The measurements were made by two participants. Afirst participant performed all measurements numbered 1 through 3 and asecond participant performed all measurements numbered 4 through 6.Measurements were taken at all 4 corners of the window surface, top left(TL), top right (TR), bottom left (BL), bottom right (BR). A table belowsummarizes the measurement results.

Exemplary EMR-Based Treatment and Window Referencing System

Stan- dard Focus Aver- Devia- Position Measurement No. age tion (μm) 1 23 4 5 6 (μm) (μm) TL Window 670 680 690.5 690 680 685.5 683 8 TR Window670 679.5 685.5 670.5 680 685.5 679 7 BL Window 690 650 644.5 700 649.5645 663 25 TL Window 700 670 660 700 670 670 678 17

The results of the measurements indicate repeatability of the exemplarywindow referencing system, even when minimum size of the image issubjectively determined by different participants. Although thesemeasurements were made in part by using judgement from humanparticipants, in some embodiments a controller is used to determineimage size and control focal region location automatically. Also, as canbeen inferred from the results, a parallelism of the window surfacerelative one or more scan axes can be calculated from measurements madeby the window referencing system. For example, one can approximate anangle between a scan axis and the window surface according to afollowing equation that assumes a small angle approximation:

$\alpha = \frac{{Z_{{ref},1} - Z_{{ref},2}}}{d_{1 - 2}}$

where: a is the angle between the scan axis and the window surface inradians; Z_(ref, 1) is the measured depth at a first location (e.g.,1^(st) corner of the window surface) in micrometers; Z_(ref, 2) is themeasured depth at a second location (e.g., 2^(nd) corner of the windowsurface) in micrometers; and d¹ ⁻² is a distance along one or more scanaxis generally perpendicular to the optical axis between the firstlocation and the second location in micrometers. The feedback andtreatment system 2100 of FIGS. 18A-18C requires a “pick off” from anoptical path (e.g., the beam splitter 1832). According to someembodiments, a “pick off” is not present.

Focal Depth Referencing Example 3

FIGS. 22A-22C show another exemplary focal depth referencing andtreatment system 2200 according to some embodiments. FIG. 22A shows atreatment system 2200 configured to direct and focus a radiation (e.g.,laser) into a target tissue. The radiation beam is provided by a fiberoptic 2210 and collimated by a collimator 2212. The radiation beam isfocused and directed through the system 2200 by an optical system. Thefocusing radiation beam is ultimately directed out of a window 2214 atthe bottom of the system 2200. The window 2214 is configured to contacta treatment tissue, such that a focal region of the focusing radiationbeam is located within the target tissue. This system 2200 does notcontain a port or a “pick off” in the optical system.

FIGS. 22B-22C illustrate the system 2200 having a removable referencingsystem 2220 attached. According to an exemplary use of the system 2200,the removable referencing system 2220 is installed prior to treatmentand used to reliably locate the focal region relative a known reference(e.g., a window surface). The removable referencing system 2220 isattached to an outside diameter of the collimator 2212. This allows anoptical axis 2222 of the referencing system 2220 to be nominally in linewith an optical axis 2224 of the treatment system. A reference radiationis generated by a reference radiation source 2226 (e.g. diode laserThorlabs PN: LPS-1064-APC-SP and a collimation lens [e.g., Edmund OpticsPN 33-020]). The reference radiation is partially reflected by a beamsplitter 2232 (e.g., 50-50 beam splitter Thorlabs PN: BSW4R-1064) anddirected along the optical axis 2222 of the referencing system. Thereference radiation is focused by a referencing objective 2233 (e.g.,Thorlabs PN: C240TME-1064).

In some versions, the referencing objective 2233 has a prescriptionapproximately equal to that of a treatment objective 2234. Thereferencing objective 2233 is in a reference stage 2235, whichtranslates the referencing objective 2233 along the optical axis 2222.The referencing objective 2233 brings the reference radiation to areference focal region along the optical axis 2222. The reference stage2235 therefore translates the reference focal region as well as thereference objective 2233. Where the reference focal region is near asurface of the window 2215 some portion of the reference radiation isreflected by the window 2215. A portion of the reflected referenceradiation is collimated by the reference objective 2233, transmittedthrough the beam splitter 2232, and imaged by an imaging lens 2236 ontoa camera sensor 2238. Likewise, a transmission radiation from thecollimator 2212 is focused by the treatment objective 2234, transmittedthrough the window 2215, a portion of the transmitted radiation iscollimated by the reference objective 2233, transmitted through the beamsplitter 2232, and imaged by the imagining lens 2236 onto the camerasensor 2238.

According to an exemplary embodiment of the system 2200, in use thereference focal region is brought to a reference position that iscoincident with an outer surface of the window 2215 by translating thereference stage 2235. A reference image captured by the camera 2238 isused to determine the location at which the reference focal region iscoincident with the outer surface of the window 2215. The referenceimage size will have a minimum value where the reference focal region iscoincident with the window 2215. At this point the referencing objective2233 has a focal plane that is generally coincident with the outersurface of the window 2215. The treatment radiation source is thenturned ON generating a transmission radiation. Although in some cases,the treatment radiation source is operated at a lower power than istypical during treatment (for example, 10%).

The transmission radiation is focused by the treatment objective 2234and transmitted through the window 2215. A portion of the transmissionradiation is collimated by the reference objective 2233, transmittedthrough the beam splitter 2232, and imaged by the imaging lens 2236 ontothe camera sensor 2238. A transmission image is detected by the camerasensor 2238 that represents a width of the transmission radiation beamat the focal plane of the referencing objective 2233 (e.g., the outersurface of the window). A treatment stage 2240 translates the treatmentobjective 2234 along the optical axis 2224. The transmission image hasminimum size where a position of a transmission focal region iscoincident with the focal plane of the referencing objective 2233.Although, the optical axis 2222 of the referencing system and theoptical axis of the treatment system 2224 are nominally aligned, in someversions it is advantageous for the two axes to be slightly displacedfrom one another. A translation stage 2242 is used in some embodimentsto displace the reference system optical axis 2222. Once, thetransmission focal region is positioned coincident with the outersurface of the window, the treatment stage can be zeroed and thereferencing system can be removed and treatment can be performed.

The example uses of feedback informed EMR-based treatment describedabove (e.g., detection of deleterious and advantageous plasma eventsduring treatment and accurate placement of the focal region) havegenerally been concerned with providing a safe and effective treatment.Additional uses of feedback informed EMR-based treatment may beconcerned with additional objectives, for example capturing anddocumenting tissue images to aid in determination of a diagnosis ordemonstrating positive treatment results.

TISSUE IMAGING EXAMPLES

EMR-based treatment informed by tissue imaging feedback has wide-ranginguses and benefits for dermatologic and aesthetic treatments. Forexample, according to some embodiments, tissue imaging allows the userto accurately target a treatment site during EMR-based treatment.Another exemplary use of tissue imaging is to provide documentation oftreatment results overtime (e.g., pre-treatment images andpost-treatment images). According to still other embodiments, tissueimaging is used to ascertain a diagnosis or a treatment plan for acondition prior to treatment, or an endpoint during a treatment. Thegoal of many exemplary EMR-based skin treatments is aesthetic (e.g.,relating to the appearance of the skin). In these cases, imaging of theskin undergoing treatment provides some of the most important feedbackto treatment stakeholders (patients and practitioners).

FIG. 23 illustrates a flow chart for a method 2300 of imaging andradiation-based treatment, according to some embodiments. The method2300 begins by illuminating a tissue with an imaging radiation 2306.Typically, illumination of the tissue is achieved in part by using anillumination source. Illumination may be performed in a number waysincluding: bright-field illumination, where the imaging radiation isprovided substantially on-axis to an imaging system and dark-fieldillumination, where the imaging radiation is provided substantiallyoff-axis to the imaging system. In some embodiments, the imagingradiation is substantially monochromatic. In other embodiments, theimaging radiation is substantially broadband (e.g., white light).

Next, an image of a view of the tissue is imaged 2310. Imaging is atleast partially performed using a focus optic (e.g., objective). Theview in some cases is a field of view of a focal region associated withthe focus optic. In some embodiments, imaging the image 2310 includesusing one more additional optics in conjunction with the focus optic.For example, the focus optic may significantly collimate light from theview and a tube lens may be used to form the image from the collimatedlight. The image may be formed at an image plane.

Next, the image is detected 2312. Typically, a detector is used todetect the image. Examples of detection include: photodetection,confocal photodetection, interferometric detection, and spectroscopicdetection. The detector may detect the image at the image plane. Theimage may be detected by an image sensor. Examples of image sensorsinclude semiconductor charge-coupled devices (CCD), active pixel sensorsin complementary metal-oxide-semiconductor (CMOS), and N-typemetal-oxides-semiconductor (NMOS). Image sensors typically output adetected image in a two-dimensional (2D) matrix of data (e.g., bitmap).

The image is then displayed 2314. Typically, the image is displayed byan electronic visual display. Examples of displays include:electroluminescent (EL) displays, liquid crystal (LC) displays,light-emitting diode (LED)-backlit liquid crystal (LC) displays,light-emitting diode (LED) displays (e.g., organic LED (OLED) displays,and active-matrix organic LED (AMOLED) displays), plasma displays, andquantum dot displays. The displayed image is viewed by a designated user(e.g., clinician). In some cases, the image is recorded and stored, forexample by the controller 2419. According, to some embodiments thedisplayed image is used to target a region of tissue needing treatment.

A target treatment region is then designated 2316 within the tissue. Insome embodiments, the target treatment region is designated based inpart on the image. For example, the target treatment region may bedesignated 2316 based upon an apparent excess of pigment (e.g., dermalmelanin) in a portion of the tissue as displayed in the image. In somecases, a clinician viewing the displayed image designates the targettreatment region. Alternatively, in some embodiments, a controllerautomatically designates the target treatment region based upon theimage. The target treatment region is typically at least partiallypresent in the image.

Finally, a treatment radiation is focused to a focal region within thetreatment region 2318. Typically, the treatment radiation is focusedusing the focus optic and configured to perform an effect within thetissue (e.g., selectively generate thermionic plasma at a chromophore;achieve a cosmetic effect). In some embodiments, parameters affectingthe treatment radiation are controlled based in part upon the image.Parameters affecting treatment with the treatment radiation aredescribed in detail above. In some embodiments, the focal region isscanned within the target treatment region

In some embodiments, the view is scanned from a first region to a secondregion of the tissue. Examples of scanning include: tipping/tilting theview, rotating the view, and translating the view. Further descriptionof relevant scanning means is described in U.S. patent application Ser.No. 16/219,809 “Electromagnetic Radiation Beam Scanning System andMethod,” to Dresser et al., incorporated herein by reference. In someembodiments, the view located at the first region overlaps with the viewlocated at the second region. In this case some of the tissue is presentin both the first region and the second region. In some otherembodiments, the view located at the first region does not overlap withthe view located at the second region. In some embodiments, scanning ofthe view is achieved with feedback related to the view position. Forexample, in some cases the view is scanned by moving the focus opticwith two linear stages. Feedback from encoders present on each linearstage may be used to infer the position of the view when located at thefirst region and/or the second region.

A second image may be imaged of the view from the second region.Typically, imaging the second image is performed in the same manner asimaging the first image 2310, only the location of the view is differentbetween the two steps. Imaging is at least partially performed using thefocus optic. The view in some cases is the field of view of the focalregion associated with the focus optic. The second image may bedetected. Typically, detecting the second image is performed in the samemanner as detecting the first image 2312, the only difference being thesecond image is detected instead of the first image.

In some cases, the first image and the second image are stitchedtogether into a stitched image (or map). The stitched image may alsoinclude additional images taken with the view located at additionalregions. The stitched image may be used to document a pre-treatmentimage of the tissue, or a post-treatment image of the tissue. Any of thefirst image the second image, and the stitched image may be taken priorto treatment and used to support a determination of a diagnosis, forexample by a medical professional. Likewise, any of the first image, thesecond image, and the stitched image may be taken during or aftertreatment to demonstrate effectiveness of treatment or to look forend-points during treatment, which can suggest treatment be ended.

Referring to FIG. 24 schematics are shown for a tissue imaging andtreatment system 2400, according to some embodiments. The imaging andtreatment system 2400 includes a focus optic 2410. The focus optic 2410(e.g., objective) is configured to image a view 2412 of a tissue 2413. Adetector 2414 is configured to detect an image 2416 formed at least inpart by the focus optic 2410. The detector 2414 is communicative with adisplay 2417. The display is configured to display the image to adesignated user (e.g., clinician). According to some embodiments, a tubelens 2418 is used in conjunction with the focus optic 2410 to form theimage 2416. The detector 2414 is communicative with a controller 2419,such that data associated with the detected image from the detector isinput to the controller 2419. The focus optic 2410 is used for deliveryof a treatment radiation 2420 as well as imaging. A scanner 2422 isconfigured to scan the view 2412. The scanner typically scans the viewin at least one dimension. In some embodiments, the scanner 2422 scansthe view in all three dimensions. Referring to FIG. 24, the scanner 2422is shown scanning the view 2412 from a first region 2424 to a secondregion 2426 of the tissue 2413.

As the scanner 2422 scans the view 2412, the focus optic 2410 images afirst image at the first region 2424 and a second image at the secondregion 2426. The first image and the second image are both detected bythe detector 2414. And, data associated with the first detected imageand the second detected image are input to the controller 2419. In someembodiments, the data associated with multiple images are stitchedtogether by the controller 2419, yielding a stitched image (or map). Thestitched image and/or one or more images can be recorded and stored bythe controller for future viewing. In some embodiments, data from one ormore images are used to determine a treatment region. According to someembodiments, determining the treatment region is done automatically bythe controller. In other embodiments, determining the treatment regionis done manually by the designated user after viewing one or moreimages.

The treatment radiation 2420 is focused to a focal region by the focusoptic 2410. And, the focal region is directed to the treatment region.According to some embodiments, the scanner 2422 is configured to scanthe focal region within the treatment region. Some embodiments of thesystem 2400 include a window 2430 that is placed in contact with asurface of the tissue 2413. The window 2430 can serve several purposes,one being to datum an outer surface of the tissue. The window 2430therefore allows the focal region to be reliably located within thetissue 2413 a predetermined depth from the surface of the tissue 2413.

FIG. 25 schematically illustrates a stitched image (or map) 2500according to some embodiments. The stitched image 2500 includes a number(e.g., 9) individual images 2510. A scan path 2520 shows a path taken bya view as it traverses a tissue. The scan path shown includes a rasterpattern although other patterns are possible (e.g., spiral). Eachindividual image 2510 is taken at a point located along the scan path.The stitched image 2500 may be formed from the individual images inseveral ways. For example, if a position of the view is estimate-ablefor each individual image (e.g., through scanner feedback), the stitchedimage 2500 may be constructed through dead-reckoning calculations.Alternatively, the stitched image 2500 may be constructed using machinevision algorithms for stitching. A first example imaging stitchingsoftware is Hugin-Panorama photo stitcher. Hugin is an open sourceproject hosted at http://hugin.Sourceforge.net. A second example imagestitching software is a Photomerge tool within Adobe Photoshop. Aparticular individual embodiment is provided below to further explaintissue imaging in an EMR treatment device.

Tissue Imaging Example 1

FIGS. 26A-26B illustrate schematics of an example tissue imaging andtreatment system 2600. FIG. 26A shows a front view of the system 2600.FIG. 26B shows a cross-sectional view of the system 2600 taken along aB-B section line in FIG. 26A.

The system 2600 includes a fiber laser 2610. The fiber laser 2610 isconfigured to output a treatment radiation. An example of a fiber laseris a Feibo 1060 nm, 40 W, 20 Khz, fiber laser from Feibo LaserTechnologies Co., Ltd. Of Shanghai, China. The treatment radiation isdirected by an optical system to a focus optic 2620 that focuses thetreatment radiation through a window 2622 to a focal region in a tissue(not shown). The optical system is configured to allow the focus optic2620 to be scanned in all three dimensions. This allows the focal regionof the treatment radiation to be scanned in all three dimensions withinthe tissue. Scanning is achieved by three separate stages eachresponsible for a single axis. An X-stage 2625 scans the focus optic inan X-axis. A Y-stage 2626, mounted to the X-stage 2625, scans the focusoptic in a Y-axis. And, a Z-stage, mounted to the Y-stage 2626, scansthe focus optic in a Z-axis (e.g., generally along an optical axis ofthe focus optic). An exemplary X-stage is a Dover MMX 50 from DoverMotion of Boxborough, Mass., USA, controlled with an Elmo DC whistleGold controller from Elmo Motion Controller Ltd. of Petach-Tikva,Israel. An exemplary Y-stage is a Q545.140 stage controlled with E 873controller both from Physik Instrumente L.P. of Auburn, Mass., USA. Anexemplary Z-stage is a New Scale 3M-FS from New Scale Technologies, Inc.of Victor, N.Y., USA.

The optical system includes a beam splitter 2630 that is configured toreflect the treatment radiation and pass other radiations (e.g., visiblelight). So, imaging radiation (e.g., visible light) from the tissue isimaged by the focus optic 2620 through the beam splitter 2630. Down beamof the beam splitter 2630, a lens assembly 2632 is located. An exampleof a lens assembly is a VarioOptic Autofocus lens module part No.:C-C-39NO-250 from Corning Inc. of Corning, N.Y., USA. The imagingradiation is further imaged by the lens assembly and finally detected bya camera 2634, and more specifically an image sensor within the camera.An example camera is a PL-D755 from PixelLink of Ontario, Canada. ThePL-D755 has an image sensor that is a SONY IMX250 CMOS having a globalshutter. In order to microscopically image very small areas, the imagingsystem shown requires illumination of the tissue.

A frame 2640 is shown with a plurality of holes 2642 throughout it.Within the holes 2642, multiple fiber optic bundles (not shown) areplaced. In an exemplary illumination scheme 12 fiber optic bundleshoused within 0.06″ diameter stainless steel tubes are placed in holes2642 positioned around the frame 2640. The fiber optic bundles convergeinto a single bundle at a distal end. The single bundle is placed inoptical communication with a light source. An exemplary light source isa daylight white 6500K 38 W light engine part number FTIII24015 fromFiberoptics Technology Incorporated of Pomfret, Conn., USA. The holes2642 are angled toward the window 2622 and therefore light from thefiber optic bundles is directed toward the tissue as it exists thebundles. Illuminating at an angle relative the optical axis of the focusoptic may be referred to as dark-field illumination. In someembodiments, dark-field illumination is advantageous as specularreflection from the window surfaces is not imaged (as glare) by thefocus optic. In other embodiments, illumination is provided generallycoaxially with the optical axis. This technique of illumination may bereferred to as bright-field illumination. Bright-field illumination isadvantageous in some embodiments, as it provides greater illuminationdensity within the view of the focus optic. In order to demonstratepracticality, images taken with the example imaging system aredescribed.

FIG. 27A shows an image 2710 taken by the example system 2600 shown inFIGS. 26A-B. This image 2710 was taken of an Air Force 1951 target. 18images like this image 2710 were taken (2 rows of 9). The 18 images werestitched together into a stitched image 2720, which is shown in FIG.27B. Stitching was automatically performed using the Photomerge tool inAdobe Photoshop. Reviewing the stitched image 2720 shows that Group 7element 6 is resolvable. Lines in Group 7 element 6 are approximately2.2 μm wide. Microscopic imaging is therefore practical using theexample system 2600 shown in FIGS. 26A-B.

ADDITIONAL EMBODIMENTS

In some embodiments, the repetition rate of the input laser beam can befaster than the decay rate of the plasma in the target tissue/targetmaterial. This can allow for continuous (e.g., temporally continuous,spatially continuous, etc.) generation of plasma. The area of thetreatment region/target region (e.g., region in which plasma isgenerated) can be controlled by changing the repetition rate of thelaser beam.

Additional embodiments include alternative imaging technologies used inconjunction with EMR-based treatment. These alternative imagingtechnologies include: microscopic imaging, wide field of view imaging,reflectance confocal imaging, optical coherence tomography imaging,optical coherence elastography imaging, coherent anti-stokes Ramanspectroscopy imaging, two-photon imaging, second harmonic generationimaging, phase conjugate imaging, photoacoustic imaging, infraredspectral imaging, and hyperspectral imaging.

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

The subject matter described herein can be implemented in digitalelectronic circuitry, or in computer software, firmware, or hardware,including the structural means disclosed in this specification andstructural equivalents thereof, or in combinations of them. The subjectmatter described herein can be implemented as one or more computerprogram products, such as one or more computer programs tangiblyembodied in an information carrier (e.g., in a machine readable storagedevice), or embodied in a propagated signal, for execution by, or tocontrol the operation of, data processing apparatus (e.g., aprogrammable processor, a computer, or multiple computers). A computerprogram (also known as a program, software, software application, orcode) can be written in any form of programming language, includingcompiled or interpreted languages, and it can be deployed in any form,including as a stand-alone program or as a module, component,subroutine, or other unit suitable for use in a computing environment. Acomputer program does not necessarily correspond to a file. A programcan be stored in a portion of a file that holds other programs or data,in a single file dedicated to the program in question, or in multiplecoordinated files (e.g., files that store one or more modules, subprograms, or portions of code). A computer program can be deployed to beexecuted on one computer or on multiple computers at one site ordistributed across multiple sites and interconnected by a communicationnetwork.

The processes and logic flows described in this specification, includingthe method steps of the subject matter described herein, can beperformed by one or more programmable processors executing one or morecomputer programs to perform functions of the subject matter describedherein by operating on input data and generating output. The processesand logic flows can also be performed by, and apparatus of the subjectmatter described herein can be implemented as, special purpose logiccircuitry, e.g., an FPGA (field programmable gate array) or an ASIC(application specific integrated circuit).

Processors suitable for the execution of a computer program include, byway of example, both general and special purpose microprocessors, andany one or more processor of any kind of digital computer. Generally, aprocessor will receive instructions and data from a read only memory ora random access memory or both. The essential elements of a computer area processor for executing instructions and one or more memory devicesfor storing instructions and data. Generally, a computer will alsoinclude, or be operatively coupled to receive data from or transfer datato, or both, one or more mass storage devices for storing data, e.g.,magnetic, magneto optical disks, or optical disks. Information carrierssuitable for embodying computer program instructions and data includeall forms of non-volatile memory, including by way of examplesemiconductor memory devices, (e.g., EPROM, EEPROM, and flash memorydevices); magnetic disks, (e.g., internal hard disks or removabledisks); magneto optical disks; and optical disks (e.g., CD and DVDdisks). The processor and the memory can be supplemented by, orincorporated in, special purpose logic circuitry.

To provide for interaction with a user, the subject matter describedherein can be implemented on a computer having a display device, e.g., aCRT (cathode ray tube) or LCD (liquid crystal display) monitor, fordisplaying information to the user and a keyboard and a pointing device,(e.g., a mouse or a trackball), by which the user can provide input tothe computer. Other kinds of devices can be used to provide forinteraction with a user as well. For example, feedback provided to theuser can be any form of sensory feedback, (e.g., visual feedback,auditory feedback, or tactile feedback), and input from the user can bereceived in any form, including acoustic, speech, or tactile input.

The techniques described herein can be implemented using one or moremodules. As used herein, the term “module” refers to computing software,firmware, hardware, and/or various combinations thereof. At a minimum,however, modules are not to be interpreted as software that is notimplemented on hardware, firmware, or recorded on a non-transitoryprocessor readable recordable storage medium (i.e., modules are notsoftware per se). Indeed “module” is to be interpreted to always includeat least some physical, non-transitory hardware such as a part of aprocessor or computer. Two different modules can share the same physicalhardware (e.g., two different modules can use the same processor andnetwork interface). The modules described herein can be combined,integrated, separated, and/or duplicated to support variousapplications. Also, a function described herein as being performed at aparticular module can be performed at one or more other modules and/orby one or more other devices instead of or in addition to the functionperformed at the particular module. Further, the modules can beimplemented across multiple devices and/or other components local orremote to one another. Additionally, the modules can be moved from onedevice and added to another device, and/or can be included in bothdevices.

The subject matter described herein can be implemented in a computingsystem that includes a back end component (e.g., a data server), amiddleware component (e.g., an application server), or a front endcomponent (e.g., a client computer having a graphical user interface ora web browser through which a user can interact with an implementationof the subject matter described herein), or any combination of such backend, middleware, and front end components. The components of the systemcan be interconnected by any form or medium of digital datacommunication, e.g., a communication network. Examples of communicationnetworks include a local area network (“LAN”) and a wide area network(“WAN”), e.g., the Internet.

Approximating language, as used herein throughout the specification andclaims, may be applied to modify any quantitative representation thatcould permissibly vary without resulting in a change in the basicfunction to which it is related. “Approximately,” “substantially,” or“about” can include numbers that fall within a range of 1%, or in someembodiments within a range of 5% of a number, or in some embodimentswithin a range of 10% of a number in either direction (greater than orless than the number) unless otherwise stated or otherwise evident fromthe context (except where such number would impermissibly exceed 100% ofa possible value). Accordingly, a value modified by a term or terms,such as “about,” “approximately,” or “substantially,” are not to belimited to the precise value specified. In at least some instances, theapproximating language may correspond to the precision of an instrumentfor measuring the value. Here and throughout the specification andclaims, range limitations may be combined and/or interchanged, suchranges are identified and include all the sub-ranges contained thereinunless context or language indicates otherwise.

The articles “a” and “an” as used herein in the specification and in theclaims, unless clearly indicated to the contrary, should be understoodto include the plural referents. Claims or descriptions that include“or” between one or more members of a group are considered satisfied ifone, more than one, or all of the group members are present in, employedin, or otherwise relevant to a given product or process unless indicatedto the contrary or otherwise evident from the context. The disclosureincludes embodiments in which exactly one member of the group is presentin, employed in, or otherwise relevant to a given product or process.The disclosure also includes embodiments in which more than one, or allof the group members are present in, employed in, or otherwise relevantto a given product or process. Furthermore, it is to be understood thatthe disclosed embodiments provide all variations, combinations, andpermutations in which one or more limitations, elements, clauses,descriptive terms, etc., from one or more of the listed claims isintroduced into another claim dependent on the same base claim (or, asrelevant, any other claim) unless otherwise indicated or unless it wouldbe evident to one of ordinary skill in the art that a contradiction orinconsistency would arise. It is contemplated that all embodimentsdescribed herein are applicable to all different aspects of thedisclosed embodiments where appropriate. It is also contemplated thatany of the embodiments or aspects can be freely combined with one ormore other such embodiments or aspects whenever appropriate. Whereelements are presented as lists, e.g., in Markush group or similarformat, it is to be understood that each subgroup of the elements isalso disclosed, and any element(s) can be removed from the group. Itshould be understood that, in general, where the disclosed embodiments,or aspects of the disclosed embodiments, is/are referred to ascomprising particular elements, features, etc., certain embodiments ofthe disclosure or aspects of the disclosure consist, or consistessentially of, such elements, features, etc. For purposes of simplicitythose embodiments have not in every case been specifically set forth inso many words herein. It should also be understood that any embodimentor aspect of the disclosure can be explicitly excluded from the claims,regardless of whether the specific exclusion is recited in thespecification. For example, any one or more active agents, additives,ingredients, optional agents, types of organism, disorders, subjects, orcombinations thereof, can be excluded.

Where ranges are given herein, embodiments of the disclosure includeembodiments in which the endpoints are included, embodiments in whichboth endpoints are excluded, and embodiments in which one endpoint isincluded and the other is excluded. It should be assumed that bothendpoints are included unless indicated otherwise. Furthermore, it is tobe understood that unless otherwise indicated or otherwise evident fromthe context and understanding of one of ordinary skill in the art,values that are expressed as ranges can assume any specific value orsubrange within the stated ranges in different embodiments of thedisclosure, to the tenth of the unit of the lower limit of the range,unless the context clearly dictates otherwise. It is also understoodthat where a series of numerical values is stated herein, the disclosureincludes embodiments that relate analogously to any intervening value orrange defined by any two values in the series, and that the lowest valuemay be taken as a minimum and the greatest value may be taken as amaximum. Numerical values, as used herein, include values expressed aspercentages.

It should be understood that, unless clearly indicated to the contrary,in any methods claimed herein that include more than one act, the orderof the acts of the method is not necessarily limited to the order inwhich the acts of the method are recited, but the disclosure includesembodiments in which the order is so limited. It should also beunderstood that unless otherwise indicated or evident from the context,any product or composition described herein may be considered“isolated”.

As used herein the term “comprising” or “comprises” is used in referenceto compositions, methods, and respective component(s) thereof, that areessential to the disclosed embodiments, yet open to the inclusion ofunspecified elements, whether essential or not.

As used herein the term “consisting essentially of” refers to thoseelements required for a given embodiment. The term permits the presenceof additional elements that do not materially affect the basic and novelor functional characteristic(s) of that embodiment of the disclosure.

The term “consisting of” refers to compositions, methods, and respectivecomponents thereof as described herein, which are exclusive of anyelement not recited in that description of the embodiment.

Although a few variations have been described in detail above, othermodifications or additions are possible.

In the descriptions above and in the claims, phrases such as “at leastone of” or “one or more of” may occur followed by a conjunctive list ofelements or features. The term “and/or” may also occur in a list of twoor more elements or features. Unless otherwise implicitly or explicitlycontradicted by the context in which it is used, such a phrase isintended to mean any of the listed elements or features individually orany of the recited elements or features in combination with any of theother recited elements or features. For example, the phrases “at leastone of A and B;” “one or more of A and B;” and “A and/or B” are eachintended to mean “A alone, B alone, or A and B together.” A similarinterpretation is also intended for lists including three or more items.For example, the phrases “at least one of A, B, and C;” “one or more ofA, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, Balone, C alone, A and B together, A and C together, B and C together, orA and B and C together.” In addition, use of the term “based on,” aboveand in the claims is intended to mean, “based at least in part on,” suchthat an unrecited feature or element is also permissible.

The subject matter described herein can be embodied in systems,apparatus, methods, and/or articles depending on the desiredconfiguration. The implementations set forth in the foregoingdescription do not represent all implementations consistent with thesubject matter described herein. Instead, they are merely some examplesconsistent with aspects related to the described subject matter.Although a few variations have been described in detail above, othermodifications or additions are possible. In particular, further featuresand/or variations can be provided in addition to those set forth herein.For example, the implementations described above can be directed tovarious combinations and sub-combinations of the disclosed featuresand/or combinations and sub-combinations of several further featuresdisclosed above. In addition, the logic flows depicted in theaccompanying figures and/or described herein do not necessarily requirethe particular order shown, or sequential order, to achieve desirableresults. Other implementations may be within the scope of the followingclaims.

What is claimed is:
 1. A system comprising: a focus optic configured tofocus an electromagnetic radiation (EMR) beam to a focal region locatedalong an optical axis; a window, intersecting the optical axis,configured to contact a surface of a tissue; an optical detectorconfigured to detect a signal radiation emanating from an interaction ofthe EMR beam with the window; a controller configured to determine areference position where a portion of the focal region is substantiallycoincident with a surface of the window; and a stage configured totranslate the focal region to a treatment position that is located at apredetermined distance from the reference position.
 2. The system ofclaim 1, wherein the focus optic and the stage are configured toposition the treatment position within a tissue.
 3. The system of claim2, wherein the treatment position is located within a dermal tissue. 4.The system of claim 2, wherein the EMR beam is configured to generate athermionic plasma at the focal region.
 5. The system of claim 1, whereinthe EMR beam comprises a pulse having a pulse duration of at least 1picosecond.
 6. The system of claim 1, wherein the focus optic is furtherconfigured to image the signal radiation incident the detector.
 7. Thesystem of claim 1, wherein the controller is further configured todetermine the reference position by: determining a transverse width ofthe EMR beam incident the surface of the window, based upon the signalradiation; and translating the focal region until the transverse widthhas a minimum value.
 8. The system of claim 1, wherein the detector isfurther configured to detect an intensity of the signal radiation, andwherein the controller is further configured to determine the referenceposition by translating the focal region until the intensity of thesignal radiation has a maximum value.
 9. The system of claim 1, whereinthe focus optic is further configured to converge a second EMR beam to asecond focal region, wherein the second EMR beam has at least one of: awavelength that is identical to a wavelength of the EMR beam or awavelength that is different to the wavelength of the EMR beam, and,wherein the second EMR beam is configured to effect a desired change inthe tissue.
 10. The system of claim 1, wherein the stage is configuredto translate the focal region by translating at least one of: the focusoptic, one or more optical elements, and the window.
 11. A methodcomprising: converging, using a focus optic, an electromagneticradiation (EMR) beam to a focal region located along an optical axis;detecting, using a detector, a signal radiation emanating from aninteraction of the EMR beam and a window intersecting the optical axis;determining, using a controller, a reference position along the opticalaxis based upon the detected signal radiation, wherein, at the referenceposition, a portion of the focal region is substantially coincident witha surface of the window; and, translating the focal region to atreatment position located a predetermined distance from the referenceposition.
 12. The method of claim 11, further comprising contacting,using the window, a surface of a tissue, such that the treatmentposition is located within the tissue.
 13. The method of claim 12,wherein the predetermined distance is configured to locate the treatmentposition within a dermal tissue.
 14. The method of claim 12, wherein theEMR beam is configured to generate a thermionic plasma in the focalregion.
 15. The method of claim 11, wherein the EMR beam comprises apulse having a pulse duration of at least 1 picosecond.
 16. The methodof claim 11, wherein detecting the signal radiation further comprisesimaging, using the focus optic, the signal radiation incident thedetector.
 17. The method of claim 11, wherein determining the referenceposition further comprises: determining, using the controller, atransverse width of the EMR beam incident the surface of the window,based upon the signal radiation; and, translating the focal region alongthe optical axis until the transverse width has a minimum value.
 18. Themethod of claim 11, wherein determining the reference position furthercomprises: detecting, using the detector, an intensity of the signalradiation; and translating the focal region until the intensity of thesignal radiation has a maximum value.
 19. The method of claim 11,further comprising: converging, using the focus optic, a second EMR beamto a second focal region, wherein the second EMR beam has at least oneof: a wavelength that is identical to a wavelength of the EMR beam or awavelength that is different to the wavelength of the EMR beam; andwherein the second EMR beam is configured to effect a desired change inthe tissue.
 20. The method of claim 11, wherein translating the focalregion further comprises translating at least one of the focus optic,one or more optical elements, and the window.